TRPV4 is a Ca2+-permeable, non-selective cation channel of the TRP vanilloid subfamily that assembles as a homotetramer in the plasma membrane, each subunit contributing an N-terminal ankyrin-repeat domain, six transmembrane helices and a pore loop. It is a polymodal sensor: it is gated by cell swelling / hypotonicity (and the attendant membrane stretch), by warmth, by acidic pH and by phorbol-ester and endogenous lipid ligands, and opening admits extracellular Ca2+ (and other cations) into the cytosol, where the Ca2+ signal can be amplified by release from internal stores. Through this activity TRPV4 acts as an osmosensor and mechanosensor: it is expressed in circumventricular-organ and hypothalamic neurons that regulate systemic osmolality and drinking, in kidney tubule and airway epithelia, in vascular and lymphatic endothelium and smooth muscle, in chondrocytes, keratinocytes, sensory (DRG) neurons and astrocytes. Its C-terminus binds the actin and microtubule cytoskeleton directly, coupling channel gating to cytoskeletal remodelling, and it partners with aquaporin-4 to drive regulatory volume decrease. Channel surface levels and signalling are tuned by interacting kinases, calmodulin and, after angiotensin-receptor activation, by beta-arrestin-1/AIP4-mediated ubiquitination and internalization. Physiological roles span osmotic and fluid-volume homeostasis, endothelial barrier/permeability and vascular tone, thermosensation, skeletal development, and metabolic and inflammatory signalling in adipose tissue.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Negative regulation of Pol II transcription (Pgc1a/Ucp1 repression). Reason: TRPV4 represses Pgc1a/Ucp1 indirectly via ERK1/2 signalling; it is not a transcriptional regulator acting at Pol II promoters, so a direct transcription term over-annotates the indirect effect. Supporting Evidence: PMID:23021218 TRPV4 negatively regulated the expression of PGC1Ξ±, UCP1, and cellular respiration. PMID:23021218 These data strongly suggest that the ERK1/2 protein kinases mediate much of the effect of TRPV4 activation on both the repression of Pgc1Ξ± expression and the induction of many chemokines/cytokines in adipocytes. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Negative regulation of Pol II transcription (Pgc1a/Ucp1 repression). Reason: TRPV4 represses Pgc1a/Ucp1 indirectly via ERK1/2 signalling; it is not a transcriptional regulator acting at Pol II promoters, so a direct transcription term over-annotates the indirect effect. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1926945 SOURCE WEAK OR INFERRED Supporting Evidence: PMID:23021218 TRPV4 negatively regulated the expression of PGC1Ξ±, UCP1, and cellular respiration. PMID:23021218 These data strongly suggest that the ERK1/2 protein kinases mediate much of the effect of TRPV4 activation on both the repression of Pgc1Ξ± expression and the induction of many chemokines/cytokines in adipocytes. |
| GO:0001666 response to hypoxia | IEP PMID:22962011 Implication of the ryanodine receptor in TRPV4-induced calci... | KEEP AS NON CORE | Summary: TRPV4 (and RyR2) protein increases in pulmonary arteries of chronically hypoxic rats. Reason: IEP expression-pattern evidence: TRPV4 is upregulated under chronic hypoxia in rat pulmonary artery; an expression response, non-core. Supporting Evidence: PMID:22962011 Western blotting experiments revealed the expression of TRPV4 and RyR2 with an increase in both receptors in pulmonary arteries from CH rats vs. Nx rats. |
| GO:0002024 diet induced thermogenesis | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: diet induced thermogenesis: TRPV4-null / antagonist-treated mice are protected from diet-induced obesity and insulin resistance. Reason: Organism-level metabolic phenotypes of TRPV4 loss arise from its adipocyte signalling role; they are downstream systemic consequences, not processes TRPV4 directly participates in. Supporting Evidence: PMID:23021218 Mice with a null mutation for TRPV4 or wild-type mice treated with a TRPV4 antagonist showed elevated thermogenesis in adipose tissues and were protected from diet-induced obesity, adipose inflammation, and insulin resistance. PMID:23021218 TRPV4 negatively regulated the expression of PGC1Ξ±, UCP1, and cellular respiration. |
| GO:0002024 diet induced thermogenesis | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: diet induced thermogenesis: TRPV4-null / antagonist-treated mice are protected from diet-induced obesity and insulin resistance. Reason: Organism-level metabolic phenotypes of TRPV4 loss arise from its adipocyte signalling role; they are downstream systemic consequences, not processes TRPV4 directly participates in. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1926945 SOURCE WEAK OR INFERRED Supporting Evidence: PMID:23021218 Mice with a null mutation for TRPV4 or wild-type mice treated with a TRPV4 antagonist showed elevated thermogenesis in adipose tissues and were protected from diet-induced obesity, adipose inflammation, and insulin resistance. PMID:23021218 TRPV4 negatively regulated the expression of PGC1Ξ±, UCP1, and cellular respiration. |
| GO:0002027 regulation of heart rate | IMP NOT PMID:23136043 An orally active TRPV4 channel blocker prevents and resolves... | UNDECIDED | Summary: NOT regulation of heart rate (IMP, PMID:23136043). Reason: Negated annotation from a paper whose full text is not available in the cache; the underlying cardiovascular measurements cannot be inspected, so the negative claim is left undecided. |
| GO:0003018 vascular process in circulatory system | IEA GO_REF:0000117 | TOO GENERAL | Summary: Vascular process in circulatory system (ARBA). Reason: Ancestor of positive regulation of vascular permeability (GO:0043117), which is asserted in this review. Supporting Evidence: PMID:23136043 TRPV4 blockade prevented the increased vascular permeability and resultant pulmonary edema associated with elevated PVP |
| GO:0003779 actin binding | IDA PMID:20657843 Importance of non-selective cation channel TRPV4 interaction... | KEEP AS NON CORE | Summary: Direct binding of the TRPV4 C-terminus to actin. Reason: MBP-TRPV4 C-terminus binds soluble and polymeric actin. Real but peripheral to channel function. Supporting Evidence: PMID:20657843 The C-terminus of TRPV4 is sufficient for interaction with actin and tubulin |
| GO:0005034 osmosensor activity | IEA GO_REF:0000107 | ACCEPT | Summary: Osmosensor: TRPV4 detects decreases in extracellular osmolarity and converts them into Ca2+ entry. Reason: Rat VR-OAC responds to hypotonicity as small as 1% within the physiological range, and knockout mice show defective central osmosensing. This is the defining sensory activity of the channel. Supporting Evidence: PMID:11081638 VR-OAC is therefore capable of detecting small osmotic-pressure changes under physiological conditions. PMID:11081638 This novel cation-selective channel is gated by exposure to hypotonicity within the physiological range. PMID:14581612 TRPV4 is necessary for the normal response to changes in osmotic pressure and functions as an osmotic sensor in the CNS |
| GO:0005034 osmosensor activity | ISO GO_REF:0000121 | ACCEPT | Summary: Osmosensor: TRPV4 detects decreases in extracellular osmolarity and converts them into Ca2+ entry. Reason: Rat VR-OAC responds to hypotonicity as small as 1% within the physiological range, and knockout mice show defective central osmosensing. This is the defining sensory activity of the channel. Supporting Evidence: PMID:11081638 VR-OAC is therefore capable of detecting small osmotic-pressure changes under physiological conditions. PMID:11081638 This novel cation-selective channel is gated by exposure to hypotonicity within the physiological range. PMID:14581612 TRPV4 is necessary for the normal response to changes in osmotic pressure and functions as an osmotic sensor in the CNS |
| GO:0005080 protein kinase C binding | IDA PMID:20657843 Importance of non-selective cation channel TRPV4 interaction... | KEEP AS NON CORE | Summary: PKCepsilon is present in the complex pulled down by the TRPV4 C-terminus from brain/F11 extracts. Reason: The pull-down shows association within a multiprotein complex rather than a demonstrated direct contact, but PKC phosphorylation and scaffolding of TRPV4 are well documented. Kept as non-core regulatory interaction. Supporting Evidence: PMID:20657843 In addition, we also detected PKCΞ΅ in the MBP-TRPV4-Ct complex, both in presence and absence of Ca2+. |
| GO:0005216 monoatomic ion channel activity | IEA GO_REF:0000002 | MODIFY | Summary: Generic ion channel term from InterPro mapping (Ion_trans domain). Reason: Correct but uninformative; the channel is a Ca2+-permeable cation channel and the gene already carries GO:0005262. Proposed replacements: calcium channel activity Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Pfam; PF00520; Ion_trans; 1. PMID:11081638 This novel cation-selective channel is gated by exposure to hypotonicity within the physiological range. PMID:11081638 These control experiments establish that Ca 2+ entry through VR-OACs is both necessary and sufficient to evoke internal Ca 2+ release |
| GO:0005261 monoatomic cation channel activity | IDA PMID:11081638 Vanilloid receptor-related osmotically activated channel (VR... | ACCEPT | Summary: Nonselective cation channel conducting K+, Na+ and Ca2+. Reason: The original rat characterization shows a large-conductance (310 pS) cation-selective, poorly Na+/K+-discriminating channel. The nonselective character is not captured by the Ca2+-specific child term, so this term is kept alongside GO:0005262. Supporting Evidence: PMID:11081638 This novel cation-selective channel is gated by exposure to hypotonicity within the physiological range. PMID:11081638 the single-channel conductance of VR-OAC is 310 pS file:rat/Trpv4/Trpv4-uniprot.txt Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity PMID:11025659 OTRPC4 forms Ca2+-permeable, nonselective cation channels that exhibit spontaneous activity in isotonic media and are rapidly activated by decreases in, and are inhibited by increases in, extracellular osmolarity |
| GO:0005261 monoatomic cation channel activity | IEA GO_REF:0000107 | ACCEPT | Summary: Nonselective cation channel conducting K+, Na+ and Ca2+. Reason: The original rat characterization shows a large-conductance (310 pS) cation-selective, poorly Na+/K+-discriminating channel. The nonselective character is not captured by the Ca2+-specific child term, so this term is kept alongside GO:0005262. Supporting Evidence: PMID:11081638 This novel cation-selective channel is gated by exposure to hypotonicity within the physiological range. PMID:11081638 the single-channel conductance of VR-OAC is 310 pS file:rat/Trpv4/Trpv4-uniprot.txt Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity PMID:11025659 OTRPC4 forms Ca2+-permeable, nonselective cation channels that exhibit spontaneous activity in isotonic media and are rapidly activated by decreases in, and are inhibited by increases in, extracellular osmolarity |
| GO:0005261 monoatomic cation channel activity | ISO GO_REF:0000121 | ACCEPT | Summary: Nonselective cation channel conducting K+, Na+ and Ca2+. Reason: The original rat characterization shows a large-conductance (310 pS) cation-selective, poorly Na+/K+-discriminating channel. The nonselective character is not captured by the Ca2+-specific child term, so this term is kept alongside GO:0005262. Supporting Evidence: PMID:11081638 This novel cation-selective channel is gated by exposure to hypotonicity within the physiological range. PMID:11081638 the single-channel conductance of VR-OAC is 310 pS file:rat/Trpv4/Trpv4-uniprot.txt Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity PMID:11025659 OTRPC4 forms Ca2+-permeable, nonselective cation channels that exhibit spontaneous activity in isotonic media and are rapidly activated by decreases in, and are inhibited by increases in, extracellular osmolarity |
| GO:0005261 monoatomic cation channel activity | ISS GO_REF:0000024 | ACCEPT | Summary: Nonselective cation channel conducting K+, Na+ and Ca2+. Reason: The original rat characterization shows a large-conductance (310 pS) cation-selective, poorly Na+/K+-discriminating channel. The nonselective character is not captured by the Ca2+-specific child term, so this term is kept alongside GO:0005262. Supporting Evidence: PMID:11081638 This novel cation-selective channel is gated by exposure to hypotonicity within the physiological range. PMID:11081638 the single-channel conductance of VR-OAC is 310 pS file:rat/Trpv4/Trpv4-uniprot.txt Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity PMID:11025659 OTRPC4 forms Ca2+-permeable, nonselective cation channels that exhibit spontaneous activity in isotonic media and are rapidly activated by decreases in, and are inhibited by increases in, extracellular osmolarity |
| GO:0005262 calcium channel activity | IBA GO_REF:0000033 | ACCEPT | Summary: Rat TRPV4 is a Ca2+-permeable cation channel; Ca2+ entry through the channel is shown directly for the rat clone. Reason: Rat VR-OAC conducts Ca2+ from the extracellular medium (no response without external Ca2+; Ca2+ entry necessary and sufficient), and UniProt records the Ca2+ transport reaction from this paper. 4alpha-PDD evokes TRPV4-dependent Ca2+ influx in rat VSMC and blockers inhibit Ca2+ influx through recombinant TRPV4. Because the channel is polymodal (hypotonicity, warmth, ligands), this general Ca2+ channel term is the appropriate core activity. Supporting Evidence: PMID:11081638 These control experiments establish that Ca 2+ entry through VR-OACs is both necessary and sufficient to evoke internal Ca 2+ release PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. file:rat/Trpv4/Trpv4-uniprot.txt Reaction=Ca(2+)(in) = Ca(2+)(out) PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells PMID:23136043 inhibits Ca(2+) influx through recombinant TRPV4 channels and native endothelial TRPV4 currents |
| GO:0005262 calcium channel activity | IDA PMID:20657843 Importance of non-selective cation channel TRPV4 interaction... | ACCEPT | Summary: Rat TRPV4 is a Ca2+-permeable cation channel; Ca2+ entry through the channel is shown directly for the rat clone. Reason: Rat VR-OAC conducts Ca2+ from the extracellular medium (no response without external Ca2+; Ca2+ entry necessary and sufficient), and UniProt records the Ca2+ transport reaction from this paper. 4alpha-PDD evokes TRPV4-dependent Ca2+ influx in rat VSMC and blockers inhibit Ca2+ influx through recombinant TRPV4. Because the channel is polymodal (hypotonicity, warmth, ligands), this general Ca2+ channel term is the appropriate core activity. Supporting Evidence: PMID:11081638 These control experiments establish that Ca 2+ entry through VR-OACs is both necessary and sufficient to evoke internal Ca 2+ release PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. file:rat/Trpv4/Trpv4-uniprot.txt Reaction=Ca(2+)(in) = Ca(2+)(out) PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells PMID:23136043 inhibits Ca(2+) influx through recombinant TRPV4 channels and native endothelial TRPV4 currents |
| GO:0005262 calcium channel activity | IEA GO_REF:0000120 | ACCEPT | Summary: Rat TRPV4 is a Ca2+-permeable cation channel; Ca2+ entry through the channel is shown directly for the rat clone. Reason: Rat VR-OAC conducts Ca2+ from the extracellular medium (no response without external Ca2+; Ca2+ entry necessary and sufficient), and UniProt records the Ca2+ transport reaction from this paper. 4alpha-PDD evokes TRPV4-dependent Ca2+ influx in rat VSMC and blockers inhibit Ca2+ influx through recombinant TRPV4. Because the channel is polymodal (hypotonicity, warmth, ligands), this general Ca2+ channel term is the appropriate core activity. Supporting Evidence: PMID:11081638 These control experiments establish that Ca 2+ entry through VR-OACs is both necessary and sufficient to evoke internal Ca 2+ release PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. file:rat/Trpv4/Trpv4-uniprot.txt Reaction=Ca(2+)(in) = Ca(2+)(out) PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells PMID:23136043 inhibits Ca(2+) influx through recombinant TRPV4 channels and native endothelial TRPV4 currents |
| GO:0005262 calcium channel activity | IMP PMID:23136043 An orally active TRPV4 channel blocker prevents and resolves... | ACCEPT | Summary: Rat TRPV4 is a Ca2+-permeable cation channel; Ca2+ entry through the channel is shown directly for the rat clone. Reason: Rat VR-OAC conducts Ca2+ from the extracellular medium (no response without external Ca2+; Ca2+ entry necessary and sufficient), and UniProt records the Ca2+ transport reaction from this paper. 4alpha-PDD evokes TRPV4-dependent Ca2+ influx in rat VSMC and blockers inhibit Ca2+ influx through recombinant TRPV4. Because the channel is polymodal (hypotonicity, warmth, ligands), this general Ca2+ channel term is the appropriate core activity. Supporting Evidence: PMID:11081638 These control experiments establish that Ca 2+ entry through VR-OACs is both necessary and sufficient to evoke internal Ca 2+ release PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. file:rat/Trpv4/Trpv4-uniprot.txt Reaction=Ca(2+)(in) = Ca(2+)(out) PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells PMID:23136043 inhibits Ca(2+) influx through recombinant TRPV4 channels and native endothelial TRPV4 currents |
| GO:0005262 calcium channel activity | ISO GO_REF:0000121 | ACCEPT | Summary: Rat TRPV4 is a Ca2+-permeable cation channel; Ca2+ entry through the channel is shown directly for the rat clone. Reason: Rat VR-OAC conducts Ca2+ from the extracellular medium (no response without external Ca2+; Ca2+ entry necessary and sufficient), and UniProt records the Ca2+ transport reaction from this paper. 4alpha-PDD evokes TRPV4-dependent Ca2+ influx in rat VSMC and blockers inhibit Ca2+ influx through recombinant TRPV4. Because the channel is polymodal (hypotonicity, warmth, ligands), this general Ca2+ channel term is the appropriate core activity. Supporting Evidence: PMID:11081638 These control experiments establish that Ca 2+ entry through VR-OACs is both necessary and sufficient to evoke internal Ca 2+ release PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. file:rat/Trpv4/Trpv4-uniprot.txt Reaction=Ca(2+)(in) = Ca(2+)(out) PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells PMID:23136043 inhibits Ca(2+) influx through recombinant TRPV4 channels and native endothelial TRPV4 currents |
| GO:0005262 calcium channel activity | ISO GO_REF:0000121 | ACCEPT | Summary: Rat TRPV4 is a Ca2+-permeable cation channel; Ca2+ entry through the channel is shown directly for the rat clone. Reason: Rat VR-OAC conducts Ca2+ from the extracellular medium (no response without external Ca2+; Ca2+ entry necessary and sufficient), and UniProt records the Ca2+ transport reaction from this paper. 4alpha-PDD evokes TRPV4-dependent Ca2+ influx in rat VSMC and blockers inhibit Ca2+ influx through recombinant TRPV4. Because the channel is polymodal (hypotonicity, warmth, ligands), this general Ca2+ channel term is the appropriate core activity. Supporting Evidence: PMID:11081638 These control experiments establish that Ca 2+ entry through VR-OACs is both necessary and sufficient to evoke internal Ca 2+ release PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. file:rat/Trpv4/Trpv4-uniprot.txt Reaction=Ca(2+)(in) = Ca(2+)(out) PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells PMID:23136043 inhibits Ca(2+) influx through recombinant TRPV4 channels and native endothelial TRPV4 currents |
| GO:0005262 calcium channel activity | ISO GO_REF:0000121 | ACCEPT | Summary: Rat TRPV4 is a Ca2+-permeable cation channel; Ca2+ entry through the channel is shown directly for the rat clone. Reason: Rat VR-OAC conducts Ca2+ from the extracellular medium (no response without external Ca2+; Ca2+ entry necessary and sufficient), and UniProt records the Ca2+ transport reaction from this paper. 4alpha-PDD evokes TRPV4-dependent Ca2+ influx in rat VSMC and blockers inhibit Ca2+ influx through recombinant TRPV4. Because the channel is polymodal (hypotonicity, warmth, ligands), this general Ca2+ channel term is the appropriate core activity. Supporting Evidence: PMID:11081638 These control experiments establish that Ca 2+ entry through VR-OACs is both necessary and sufficient to evoke internal Ca 2+ release PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. file:rat/Trpv4/Trpv4-uniprot.txt Reaction=Ca(2+)(in) = Ca(2+)(out) PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells PMID:23136043 inhibits Ca(2+) influx through recombinant TRPV4 channels and native endothelial TRPV4 currents |
| GO:0005515 protein binding | IPI PMID:21262839 An aquaporin-4/transient receptor potential vanilloid 4 (AQP... | REMOVE | Summary: Bare protein binding (IPI with AQP4). Reason: Uninformative protein-binding term per the protein-binding policy. The specific AQP4/TRPV4 complex (rat astrocyte osmosensing) is captured in core functions and suggested questions. Supporting Evidence: PMID:21262839 Coimmunoprecipitation (co-IP) analyses of whole rat brain extracts indicate that TRPV4 and AQP4 form a molecular complex |
| GO:0005515 protein binding | IPI PMID:21262839 An aquaporin-4/transient receptor potential vanilloid 4 (AQP... | REMOVE | Summary: Bare protein binding (IPI with AQP4). Reason: Uninformative protein-binding term per the protein-binding policy. The specific AQP4/TRPV4 complex (rat astrocyte osmosensing) is captured in core functions and suggested questions. Supporting Evidence: PMID:21262839 Coimmunoprecipitation (co-IP) analyses of whole rat brain extracts indicate that TRPV4 and AQP4 form a molecular complex |
| GO:0005516 calmodulin binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Calmodulin binding (via the ankyrin-repeat region / C-terminus), transferred from human TRPV4. Reason: Ca2+-calmodulin binding regulates TRPV4 gating in human/mouse; UniProt records it by similarity. A regulatory interaction, not the core activity. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Interacts with calmodulin |
| GO:0005516 calmodulin binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Calmodulin binding (via the ankyrin-repeat region / C-terminus), transferred from human TRPV4. Reason: Ca2+-calmodulin binding regulates TRPV4 gating in human/mouse; UniProt records it by similarity. A regulatory interaction, not the core activity. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Interacts with calmodulin |
| GO:0005516 calmodulin binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Calmodulin binding (via the ankyrin-repeat region / C-terminus), transferred from human TRPV4. Reason: Ca2+-calmodulin binding regulates TRPV4 gating in human/mouse; UniProt records it by similarity. A regulatory interaction, not the core activity. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Interacts with calmodulin |
| GO:0005737 cytoplasm | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Cytoplasm, transferred from pig TRPV4. Reason: TRPV4 is an integral membrane protein; intracellular signal reflects biosynthetic (ER) or internalized vesicle pools (e.g. after angiotensin-induced endocytosis), not a cytosolic location. Better captured by plasma membrane / ER rows. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: RGD:13967072 SOURCE WEAK OR INFERRED Supporting Evidence: PMID:20650893 TRPV4 was localized at the cell surface in non-stimulated cells PMID:20650893 angiotensin-induced ubiquitination of TRPV4 serves as a signal for its internalization but not its degradation |
| GO:0005783 endoplasmic reticulum | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Endoplasmic reticulum, where TRPV4 tetramers are assembled before export. Reason: Root-organelle row checked: the human source places tetramer assembly mainly in the ER (UniProt note). This is a biosynthetic location, not where the channel works, so it is kept but non-core. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Assembly of the putative homotetramer occurs primarily in the endoplasmic reticulum. |
| GO:0005881 cytoplasmic microtubule | IDA PMID:20657843 Importance of non-selective cation channel TRPV4 interaction... | KEEP AS NON CORE | Summary: TRPV4 colocalizes with submembranous cytoplasmic microtubules in F11 cells. Reason: Colocalization of TRPV4 with microtubules along neurite-like structures; peripheral. Supporting Evidence: PMID:20657843 Often these microtubule ends extended to the plasma membrane and seemed to be stabilized at the membranous regions containing TRPV4. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane is where the channel acts. Reason: eGFP-rat VR-OAC localizes to the plasma membrane; endogenous TRPV4 is at the surface of rat VSMC (immunostaining, surface biotinylation) and a biotinylatable pool forms the AQP4 complex in rat astrocytes. Supporting Evidence: PMID:11081638 Confocal microscopy of transiently and stably transfected cells indicated that both the intact and deleted fusion proteins were localized to the plasma membrane. PMID:20650893 TRPV4 was localized at the cell surface in non-stimulated cells PMID:21262839 The TRPV4 pool that is immunoprecipitated by the AQP4 antibody can be subjected to biotinylation, indicating that AQP4 interacts with a plasma membrane pool of TRPV4 |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Plasma membrane is where the channel acts. Reason: eGFP-rat VR-OAC localizes to the plasma membrane; endogenous TRPV4 is at the surface of rat VSMC (immunostaining, surface biotinylation) and a biotinylatable pool forms the AQP4 complex in rat astrocytes. Supporting Evidence: PMID:11081638 Confocal microscopy of transiently and stably transfected cells indicated that both the intact and deleted fusion proteins were localized to the plasma membrane. PMID:20650893 TRPV4 was localized at the cell surface in non-stimulated cells PMID:21262839 The TRPV4 pool that is immunoprecipitated by the AQP4 antibody can be subjected to biotinylation, indicating that AQP4 interacts with a plasma membrane pool of TRPV4 |
| GO:0005886 plasma membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Plasma membrane is where the channel acts. Reason: eGFP-rat VR-OAC localizes to the plasma membrane; endogenous TRPV4 is at the surface of rat VSMC (immunostaining, surface biotinylation) and a biotinylatable pool forms the AQP4 complex in rat astrocytes. Supporting Evidence: PMID:11081638 Confocal microscopy of transiently and stably transfected cells indicated that both the intact and deleted fusion proteins were localized to the plasma membrane. PMID:20650893 TRPV4 was localized at the cell surface in non-stimulated cells PMID:21262839 The TRPV4 pool that is immunoprecipitated by the AQP4 antibody can be subjected to biotinylation, indicating that AQP4 interacts with a plasma membrane pool of TRPV4 |
| GO:0005886 plasma membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Plasma membrane is where the channel acts. Reason: eGFP-rat VR-OAC localizes to the plasma membrane; endogenous TRPV4 is at the surface of rat VSMC (immunostaining, surface biotinylation) and a biotinylatable pool forms the AQP4 complex in rat astrocytes. Supporting Evidence: PMID:11081638 Confocal microscopy of transiently and stably transfected cells indicated that both the intact and deleted fusion proteins were localized to the plasma membrane. PMID:20650893 TRPV4 was localized at the cell surface in non-stimulated cells PMID:21262839 The TRPV4 pool that is immunoprecipitated by the AQP4 antibody can be subjected to biotinylation, indicating that AQP4 interacts with a plasma membrane pool of TRPV4 |
| GO:0005886 plasma membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Plasma membrane is where the channel acts. Reason: eGFP-rat VR-OAC localizes to the plasma membrane; endogenous TRPV4 is at the surface of rat VSMC (immunostaining, surface biotinylation) and a biotinylatable pool forms the AQP4 complex in rat astrocytes. Supporting Evidence: PMID:11081638 Confocal microscopy of transiently and stably transfected cells indicated that both the intact and deleted fusion proteins were localized to the plasma membrane. PMID:20650893 TRPV4 was localized at the cell surface in non-stimulated cells PMID:21262839 The TRPV4 pool that is immunoprecipitated by the AQP4 antibody can be subjected to biotinylation, indicating that AQP4 interacts with a plasma membrane pool of TRPV4 |
| GO:0005886 plasma membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Plasma membrane is where the channel acts. Reason: eGFP-rat VR-OAC localizes to the plasma membrane; endogenous TRPV4 is at the surface of rat VSMC (immunostaining, surface biotinylation) and a biotinylatable pool forms the AQP4 complex in rat astrocytes. Supporting Evidence: PMID:11081638 Confocal microscopy of transiently and stably transfected cells indicated that both the intact and deleted fusion proteins were localized to the plasma membrane. PMID:20650893 TRPV4 was localized at the cell surface in non-stimulated cells PMID:21262839 The TRPV4 pool that is immunoprecipitated by the AQP4 antibody can be subjected to biotinylation, indicating that AQP4 interacts with a plasma membrane pool of TRPV4 |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Plasma membrane is where the channel acts. Reason: eGFP-rat VR-OAC localizes to the plasma membrane; endogenous TRPV4 is at the surface of rat VSMC (immunostaining, surface biotinylation) and a biotinylatable pool forms the AQP4 complex in rat astrocytes. Supporting Evidence: PMID:11081638 Confocal microscopy of transiently and stably transfected cells indicated that both the intact and deleted fusion proteins were localized to the plasma membrane. PMID:20650893 TRPV4 was localized at the cell surface in non-stimulated cells PMID:21262839 The TRPV4 pool that is immunoprecipitated by the AQP4 antibody can be subjected to biotinylation, indicating that AQP4 interacts with a plasma membrane pool of TRPV4 |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Plasma membrane is where the channel acts. Reason: eGFP-rat VR-OAC localizes to the plasma membrane; endogenous TRPV4 is at the surface of rat VSMC (immunostaining, surface biotinylation) and a biotinylatable pool forms the AQP4 complex in rat astrocytes. Supporting Evidence: PMID:11081638 Confocal microscopy of transiently and stably transfected cells indicated that both the intact and deleted fusion proteins were localized to the plasma membrane. PMID:20650893 TRPV4 was localized at the cell surface in non-stimulated cells PMID:21262839 The TRPV4 pool that is immunoprecipitated by the AQP4 antibody can be subjected to biotinylation, indicating that AQP4 interacts with a plasma membrane pool of TRPV4 |
| GO:0005912 adherens junction | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Adherens junctions of keratinocytes (with beta-catenin/E-cadherin), from mouse. Reason: Mouse keratinocyte data (via UniProt by similarity) place TRPV4 at adherens junctions; tissue-specific, non-core. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Cell junction, adherens junction file:rat/Trpv4/Trpv4-uniprot.txt Promotes cell-cell junction formation in skin keratinocytes |
| GO:0005912 adherens junction | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Adherens junctions of keratinocytes (with beta-catenin/E-cadherin), from mouse. Reason: Mouse keratinocyte data (via UniProt by similarity) place TRPV4 at adherens junctions; tissue-specific, non-core. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Cell junction, adherens junction file:rat/Trpv4/Trpv4-uniprot.txt Promotes cell-cell junction formation in skin keratinocytes |
| GO:0005912 adherens junction | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Adherens junctions of keratinocytes (with beta-catenin/E-cadherin), from mouse. Reason: Mouse keratinocyte data (via UniProt by similarity) place TRPV4 at adherens junctions; tissue-specific, non-core. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Cell junction, adherens junction file:rat/Trpv4/Trpv4-uniprot.txt Promotes cell-cell junction formation in skin keratinocytes |
| GO:0005925 focal adhesion | IDA PMID:20657843 Importance of non-selective cation channel TRPV4 interaction... | MARK AS OVER ANNOTATED | Summary: TRPV4-GFP at actin-rich structures that "resemble focal adhesion points" in F11 cells. Reason: The paper does not use a focal adhesion marker and describes only resemblance; the original rat VR-OAC study found TRPV4 clusters that did not colocalize with paxillin-labelled focal adhesions. The focal adhesion claim is overstated. Supporting Evidence: PMID:20657843 We also noted co-localization at actin-rich structures, which resemble focal adhesion points PMID:11081638 The fusion proteins sometimes produced membrane-associated fluorescent clusters that did not colocalize with focal adhesion points visualized by paxillin immunolabeling |
| GO:0005929 cilium | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Primary/motile cilia (e.g. cholangiocytes, renal epithelia, airway). Reason: UniProt records ciliary localization and a TRPV4-PKD2 ciliary channel by similarity; plausible for rat, tissue-specific, non-core. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Together with PKD2, forms mechano- and thermosensitive channels in cilium |
| GO:0005929 cilium | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Primary/motile cilia (e.g. cholangiocytes, renal epithelia, airway). Reason: UniProt records ciliary localization and a TRPV4-PKD2 ciliary channel by similarity; plausible for rat, tissue-specific, non-core. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Together with PKD2, forms mechano- and thermosensitive channels in cilium |
| GO:0005929 cilium | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Primary/motile cilia (e.g. cholangiocytes, renal epithelia, airway). Reason: UniProt records ciliary localization and a TRPV4-PKD2 ciliary channel by similarity; plausible for rat, tissue-specific, non-core. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Together with PKD2, forms mechano- and thermosensitive channels in cilium |
| GO:0005929 cilium | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Primary/motile cilia (e.g. cholangiocytes, renal epithelia, airway). Reason: UniProt records ciliary localization and a TRPV4-PKD2 ciliary channel by similarity; plausible for rat, tissue-specific, non-core. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Together with PKD2, forms mechano- and thermosensitive channels in cilium |
| GO:0006811 monoatomic ion transport | IEA GO_REF:0000002 | MODIFY | Summary: monoatomic ion transport: correct for TRPV4, but a parent of calcium ion import across plasma membrane. Reason: TRPV4 conducts extracellular Ca2+ into the cytosol across the plasma membrane; GO:0098703 is an is_a descendant of GO:0006811 (monoatomic ion transport) and is already annotated (IBA). Proposed replacements: calcium ion import across plasma membrane Supporting Evidence: PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells |
| GO:0006816 calcium ion transport | IEA GO_REF:0000107 | MODIFY | Summary: calcium ion transport: correct for TRPV4, but a parent of calcium ion import across plasma membrane. Reason: TRPV4 conducts extracellular Ca2+ into the cytosol across the plasma membrane; GO:0098703 is an is_a descendant of GO:0006816 (calcium ion transport) and is already annotated (IBA). Proposed replacements: calcium ion import across plasma membrane Supporting Evidence: PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells |
| GO:0006816 calcium ion transport | ISO GO_REF:0000121 | MODIFY | Summary: calcium ion transport: correct for TRPV4, but a parent of calcium ion import across plasma membrane. Reason: TRPV4 conducts extracellular Ca2+ into the cytosol across the plasma membrane; GO:0098703 is an is_a descendant of GO:0006816 (calcium ion transport) and is already annotated (IBA). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9HBA0 SUPPORTS TRANSFER Proposed replacements: calcium ion import across plasma membrane Supporting Evidence: PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells |
| GO:0006874 intracellular calcium ion homeostasis | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: TRPV4-mediated Ca2+ influx contributes to cellular Ca2+ homeostasis. Reason: Ca2+ entry through TRPV4 shapes cytosolic Ca2+ (and is restrained by beta-arrestin-dependent internalization to avoid excessive Ca2+ signalling); homeostasis is a broad systemic outcome rather than the channel activity itself. Supporting Evidence: PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells PMID:20650893 angiotensin-induced ubiquitination of TRPV4 serves as a signal for its internalization but not its degradation |
| GO:0006874 intracellular calcium ion homeostasis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: TRPV4-mediated Ca2+ influx contributes to cellular Ca2+ homeostasis. Reason: Ca2+ entry through TRPV4 shapes cytosolic Ca2+ (and is restrained by beta-arrestin-dependent internalization to avoid excessive Ca2+ signalling); homeostasis is a broad systemic outcome rather than the channel activity itself. Supporting Evidence: PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells PMID:20650893 angiotensin-induced ubiquitination of TRPV4 serves as a signal for its internalization but not its degradation |
| GO:0006874 intracellular calcium ion homeostasis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: TRPV4-mediated Ca2+ influx contributes to cellular Ca2+ homeostasis. Reason: Ca2+ entry through TRPV4 shapes cytosolic Ca2+ (and is restrained by beta-arrestin-dependent internalization to avoid excessive Ca2+ signalling); homeostasis is a broad systemic outcome rather than the channel activity itself. Supporting Evidence: PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells PMID:20650893 angiotensin-induced ubiquitination of TRPV4 serves as a signal for its internalization but not its degradation |
| GO:0006874 intracellular calcium ion homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: TRPV4-mediated Ca2+ influx contributes to cellular Ca2+ homeostasis. Reason: Ca2+ entry through TRPV4 shapes cytosolic Ca2+ (and is restrained by beta-arrestin-dependent internalization to avoid excessive Ca2+ signalling); homeostasis is a broad systemic outcome rather than the channel activity itself. Supporting Evidence: PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells PMID:20650893 angiotensin-induced ubiquitination of TRPV4 serves as a signal for its internalization but not its degradation |
| GO:0006874 intracellular calcium ion homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: TRPV4-mediated Ca2+ influx contributes to cellular Ca2+ homeostasis. Reason: Ca2+ entry through TRPV4 shapes cytosolic Ca2+ (and is restrained by beta-arrestin-dependent internalization to avoid excessive Ca2+ signalling); homeostasis is a broad systemic outcome rather than the channel activity itself. Supporting Evidence: PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells PMID:20650893 angiotensin-induced ubiquitination of TRPV4 serves as a signal for its internalization but not its degradation |
| GO:0006950 response to stress | IEA GO_REF:0000117 | TOO GENERAL | Summary: Generic response to stress from an ARBA rule. Reason: Ancestor of the specific osmotic/hypotonic response terms asserted here. Supporting Evidence: PMID:11081638 Upon osmotic stimulation of transfected cells, intracellular fluorescence increased significantly within seconds under hypotonic but not hypertonic conditions |
| GO:0006970 response to osmotic stress | ISO GO_REF:0000121 | TOO GENERAL | Summary: Response to osmotic stress (acts upstream), from mouse. Reason: Parent of the specific hypotonic response and osmosensory signaling pathway asserted here; TRPV4 responds to osmotic change but the general term is uninformative. Supporting Evidence: PMID:11081638 Upon osmotic stimulation of transfected cells, intracellular fluorescence increased significantly within seconds under hypotonic but not hypertonic conditions PMID:11081638 VR-OAC is therefore capable of detecting small osmotic-pressure changes under physiological conditions. |
| GO:0006971 hypotonic response | IDA PMID:11081638 Vanilloid receptor-related osmotically activated channel (VR... | MODIFY | Summary: Hypotonicity opens rat VR-OAC (the defining rat finding). Reason: The rat evidence is at the cellular level (CHO cells); GO:0071476 cellular hypotonic response is the is_a descendant that matches the assay and is already annotated. Proposed replacements: cellular hypotonic response Supporting Evidence: PMID:11081638 Upon osmotic stimulation of transfected cells, intracellular fluorescence increased significantly within seconds under hypotonic but not hypertonic conditions PMID:11081638 This novel cation-selective channel is gated by exposure to hypotonicity within the physiological range. |
| GO:0007015 actin filament organization | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: TRPV4 activation reorganizes actin (lamellipodia to filopodia) in F11 cells. Reason: Live imaging shows 4alpha-PDD-driven actin remodelling; the C-terminus binds actin directly. A cytoskeletal regulatory output, non-core. Supporting Evidence: PMID:20657843 We observed that activation of TRPV4 by 4Ξ±PDD results in rapid change of lamellipodia to filopodia and/or further elongation of filopodial structures PMID:20657843 The C-terminus of TRPV4 is sufficient for interaction with actin and tubulin |
| GO:0007015 actin filament organization | IDA PMID:20657843 Importance of non-selective cation channel TRPV4 interaction... | KEEP AS NON CORE | Summary: TRPV4 activation reorganizes actin (lamellipodia to filopodia) in F11 cells. Reason: Live imaging shows 4alpha-PDD-driven actin remodelling; the C-terminus binds actin directly. A cytoskeletal regulatory output, non-core. Supporting Evidence: PMID:20657843 We observed that activation of TRPV4 by 4Ξ±PDD results in rapid change of lamellipodia to filopodia and/or further elongation of filopodial structures PMID:20657843 The C-terminus of TRPV4 is sufficient for interaction with actin and tubulin |
| GO:0007015 actin filament organization | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: TRPV4 activation reorganizes actin (lamellipodia to filopodia) in F11 cells. Reason: Live imaging shows 4alpha-PDD-driven actin remodelling; the C-terminus binds actin directly. A cytoskeletal regulatory output, non-core. Supporting Evidence: PMID:20657843 We observed that activation of TRPV4 by 4Ξ±PDD results in rapid change of lamellipodia to filopodia and/or further elongation of filopodial structures PMID:20657843 The C-terminus of TRPV4 is sufficient for interaction with actin and tubulin |
| GO:0007043 cell-cell junction assembly | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cell-cell junction assembly in keratinocytes (mouse/human). Reason: TRPV4 promotes adherens-junction formation in keratinocytes (UniProt by similarity). Tissue-specific, non-core. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Promotes cell-cell junction formation in skin keratinocytes file:rat/Trpv4/Trpv4-uniprot.txt Cell junction, adherens junction |
| GO:0007043 cell-cell junction assembly | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cell-cell junction assembly in keratinocytes (mouse/human). Reason: TRPV4 promotes adherens-junction formation in keratinocytes (UniProt by similarity). Tissue-specific, non-core. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Promotes cell-cell junction formation in skin keratinocytes file:rat/Trpv4/Trpv4-uniprot.txt Cell junction, adherens junction |
| GO:0007043 cell-cell junction assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cell-cell junction assembly in keratinocytes (mouse/human). Reason: TRPV4 promotes adherens-junction formation in keratinocytes (UniProt by similarity). Tissue-specific, non-core. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Promotes cell-cell junction formation in skin keratinocytes file:rat/Trpv4/Trpv4-uniprot.txt Cell junction, adherens junction |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | IDA PMID:20650893 Arresting a transient receptor potential (TRP) channel: beta... | ACCEPT | Summary: Opening TRPV4 raises cytosolic Ca2+ in rat cells (VSMC, PASMC, astrocytes). Reason: Direct consequence of the channel activity: 4alpha-PDD raises [Ca2+]i in rat PASMC and VSMC, and TRPV4 knockdown abolishes the hypotonicity-evoked Ca2+ rise in rat astrocytes. Supporting Evidence: PMID:22962011 Activation of TRPV4 with the specific agonist 4Ξ±-phorbol-12,13-didecanoate (4Ξ±-PDD, 5 ΞΌM) increased the intracellular calcium concentration ([Ca(2+)](i)). PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells PMID:21262839 showed that TRPV4 is necessary for hypotonicity-elicited [Ca 2+ ] o influx ( Fig. 2 B β D ) and RVD ( Fig. 2 E ) |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | IEA GO_REF:0000107 | ACCEPT | Summary: Opening TRPV4 raises cytosolic Ca2+ in rat cells (VSMC, PASMC, astrocytes). Reason: Direct consequence of the channel activity: 4alpha-PDD raises [Ca2+]i in rat PASMC and VSMC, and TRPV4 knockdown abolishes the hypotonicity-evoked Ca2+ rise in rat astrocytes. Supporting Evidence: PMID:22962011 Activation of TRPV4 with the specific agonist 4Ξ±-phorbol-12,13-didecanoate (4Ξ±-PDD, 5 ΞΌM) increased the intracellular calcium concentration ([Ca(2+)](i)). PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells PMID:21262839 showed that TRPV4 is necessary for hypotonicity-elicited [Ca 2+ ] o influx ( Fig. 2 B β D ) and RVD ( Fig. 2 E ) |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | ISO GO_REF:0000121 | ACCEPT | Summary: Opening TRPV4 raises cytosolic Ca2+ in rat cells (VSMC, PASMC, astrocytes). Reason: Direct consequence of the channel activity: 4alpha-PDD raises [Ca2+]i in rat PASMC and VSMC, and TRPV4 knockdown abolishes the hypotonicity-evoked Ca2+ rise in rat astrocytes. Supporting Evidence: PMID:22962011 Activation of TRPV4 with the specific agonist 4Ξ±-phorbol-12,13-didecanoate (4Ξ±-PDD, 5 ΞΌM) increased the intracellular calcium concentration ([Ca(2+)](i)). PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells PMID:21262839 showed that TRPV4 is necessary for hypotonicity-elicited [Ca 2+ ] o influx ( Fig. 2 B β D ) and RVD ( Fig. 2 E ) |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | ISO GO_REF:0000121 | ACCEPT | Summary: Opening TRPV4 raises cytosolic Ca2+ in rat cells (VSMC, PASMC, astrocytes). Reason: Direct consequence of the channel activity: 4alpha-PDD raises [Ca2+]i in rat PASMC and VSMC, and TRPV4 knockdown abolishes the hypotonicity-evoked Ca2+ rise in rat astrocytes. Supporting Evidence: PMID:22962011 Activation of TRPV4 with the specific agonist 4Ξ±-phorbol-12,13-didecanoate (4Ξ±-PDD, 5 ΞΌM) increased the intracellular calcium concentration ([Ca(2+)](i)). PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells PMID:21262839 showed that TRPV4 is necessary for hypotonicity-elicited [Ca 2+ ] o influx ( Fig. 2 B β D ) and RVD ( Fig. 2 E ) |
| GO:0007231 osmosensory signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Osmosensory signaling: TRPV4 transduces extracellular osmolarity changes into intracellular Ca2+ signals. Reason: IBA at the TRP node plus direct rat and knockout-mouse evidence that TRPV4 is the osmosensor initiating the signaling cascade. Supporting Evidence: PMID:11081638 VR-OAC is therefore capable of detecting small osmotic-pressure changes under physiological conditions. PMID:14581612 TRPV4 is necessary for the normal response to changes in osmotic pressure and functions as an osmotic sensor in the CNS PMID:21262839 showed that TRPV4 is necessary for hypotonicity-elicited [Ca 2+ ] o influx ( Fig. 2 B β D ) and RVD ( Fig. 2 E ) |
| GO:0007231 osmosensory signaling pathway | ISO GO_REF:0000121 | ACCEPT | Summary: Osmosensory signaling: TRPV4 transduces extracellular osmolarity changes into intracellular Ca2+ signals. Reason: IBA at the TRP node plus direct rat and knockout-mouse evidence that TRPV4 is the osmosensor initiating the signaling cascade. Supporting Evidence: PMID:11081638 VR-OAC is therefore capable of detecting small osmotic-pressure changes under physiological conditions. PMID:14581612 TRPV4 is necessary for the normal response to changes in osmotic pressure and functions as an osmotic sensor in the CNS PMID:21262839 showed that TRPV4 is necessary for hypotonicity-elicited [Ca 2+ ] o influx ( Fig. 2 B β D ) and RVD ( Fig. 2 E ) |
| GO:0007231 osmosensory signaling pathway | ISO GO_REF:0000121 | ACCEPT | Summary: Osmosensory signaling: TRPV4 transduces extracellular osmolarity changes into intracellular Ca2+ signals. Reason: IBA at the TRP node plus direct rat and knockout-mouse evidence that TRPV4 is the osmosensor initiating the signaling cascade. Supporting Evidence: PMID:11081638 VR-OAC is therefore capable of detecting small osmotic-pressure changes under physiological conditions. PMID:14581612 TRPV4 is necessary for the normal response to changes in osmotic pressure and functions as an osmotic sensor in the CNS PMID:21262839 showed that TRPV4 is necessary for hypotonicity-elicited [Ca 2+ ] o influx ( Fig. 2 B β D ) and RVD ( Fig. 2 E ) |
| GO:0008017 microtubule binding | IDA PMID:20657843 Importance of non-selective cation channel TRPV4 interaction... | KEEP AS NON CORE | Summary: TRPV4 C-terminus binds microtubules. Reason: MBP-TRPV4-Ct co-sediments with Taxol-stabilized and freshly polymerized microtubules. Supporting Evidence: PMID:20657843 We observed that MBP-TRPV4-Ct but not MBP alone co-sedimented with Taxol-stabilized polymerized microtubules PMID:20657843 The C-terminus of TRPV4 is sufficient for interaction with actin and tubulin |
| GO:0008217 regulation of blood pressure | IMP NOT PMID:23136043 An orally active TRPV4 channel blocker prevents and resolves... | UNDECIDED | Summary: NOT regulation of blood pressure (IMP, PMID:23136043). Reason: Negated annotation from a paper whose full text is not available in the cache; the underlying cardiovascular measurements cannot be inspected, so the negative claim is left undecided. |
| GO:0009986 cell surface | IDA PMID:20650893 Arresting a transient receptor potential (TRP) channel: beta... | MODIFY | Summary: TRPV4 detected at the cell surface of rat aortic smooth muscle cells. Reason: The paper uses immunostaining and surface biotinylation of a multipass channel; the precise location is the plasma membrane (GO:0005886), which the gene already carries. Proposed replacements: plasma membrane Supporting Evidence: PMID:20650893 TRPV4 was localized at the cell surface in non-stimulated cells PMID:20650893 AT1aR and TRPV4 form a constitutive complex in the plasma membrane |
| GO:0010628 positive regulation of gene expression | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Positive regulation of gene expression (adipocyte, electronic/ISO). Reason: Vague parent of the specific chemokine/cytokine production terms; TRPV4 changes gene expression indirectly through ERK1/2, so the general term adds no information. Supporting Evidence: PMID:23021218 Knock-down of TRPV4 had a profound inhibitory effect on a whole array of chemokines, such as Ccl2 (Mcp1), Ccl3 (Mip1Ξ±), Ccl5 (Rantes), Ccl7 (Mcp3), Cxcl1 (KC), Ccl8, Cxcl5 and Cxcl10 and cytokines such as Il6, Saa3 and Thrombospondin (Figure 3A). PMID:23021218 These data strongly suggest that the ERK1/2 protein kinases mediate much of the effect of TRPV4 activation on both the repression of Pgc1Ξ± expression and the induction of many chemokines/cytokines in adipocytes. |
| GO:0010628 positive regulation of gene expression | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Positive regulation of gene expression (adipocyte, electronic/ISO). Reason: Vague parent of the specific chemokine/cytokine production terms; TRPV4 changes gene expression indirectly through ERK1/2, so the general term adds no information. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1926945 SOURCE WEAK OR INFERRED Supporting Evidence: PMID:23021218 Knock-down of TRPV4 had a profound inhibitory effect on a whole array of chemokines, such as Ccl2 (Mcp1), Ccl3 (Mip1Ξ±), Ccl5 (Rantes), Ccl7 (Mcp3), Cxcl1 (KC), Ccl8, Cxcl5 and Cxcl10 and cytokines such as Il6, Saa3 and Thrombospondin (Figure 3A). PMID:23021218 These data strongly suggest that the ERK1/2 protein kinases mediate much of the effect of TRPV4 activation on both the repression of Pgc1Ξ± expression and the induction of many chemokines/cytokines in adipocytes. |
| GO:0010759 positive regulation of macrophage chemotaxis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of macrophage chemotaxis (adipose inflammation). Reason: Downstream of TRPV4-driven adipocyte chemokine secretion; a tissue inflammatory output, non-core. Supporting Evidence: PMID:23021218 Knock-down of TRPV4 had a profound inhibitory effect on a whole array of chemokines, such as Ccl2 (Mcp1), Ccl3 (Mip1Ξ±), Ccl5 (Rantes), Ccl7 (Mcp3), Cxcl1 (KC), Ccl8, Cxcl5 and Cxcl10 and cytokines such as Il6, Saa3 and Thrombospondin (Figure 3A). |
| GO:0010759 positive regulation of macrophage chemotaxis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of macrophage chemotaxis (adipose inflammation). Reason: Downstream of TRPV4-driven adipocyte chemokine secretion; a tissue inflammatory output, non-core. Supporting Evidence: PMID:23021218 Knock-down of TRPV4 had a profound inhibitory effect on a whole array of chemokines, such as Ccl2 (Mcp1), Ccl3 (Mip1Ξ±), Ccl5 (Rantes), Ccl7 (Mcp3), Cxcl1 (KC), Ccl8, Cxcl5 and Cxcl10 and cytokines such as Il6, Saa3 and Thrombospondin (Figure 3A). |
| GO:0010977 negative regulation of neuron projection development | IDA PMID:20657843 Importance of non-selective cation channel TRPV4 interaction... | KEEP AS NON CORE | Summary: TRPV4 activation shortens neurites of rat IB4+ DRG neurons. Reason: Prolonged agonist exposure reduces neurite outgrowth in nociceptors (IDA), consistent with the cytoskeletal role. Non-core. Supporting Evidence: PMID:20657843 majority of the IB4-positive neurons developed much shorter neurites if at all |
| GO:0010977 negative regulation of neuron projection development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: TRPV4 activation shortens neurites of rat IB4+ DRG neurons. Reason: Prolonged agonist exposure reduces neurite outgrowth in nociceptors (IDA), consistent with the cytoskeletal role. Non-core. Supporting Evidence: PMID:20657843 majority of the IB4-positive neurons developed much shorter neurites if at all |
| GO:0015275 stretch-activated, monoatomic cation-selective, calcium channel activity | IEA GO_REF:0000107 | ACCEPT | Summary: Mechanosensitive (osmotic swelling / membrane stretch) gating of the TRPV4 Ca2+-permeable cation channel. Reason: TRPV4 is gated by hypotonic cell swelling, presumably through membrane stretch, and conducts Ca2+. This descendant of calcium channel activity describes the osmo/mechanically gated mode; it is accepted alongside the general term because the channel is polymodal and the direct-stretch mechanism remains debated. Supporting Evidence: PMID:11081638 Our experiments establish that osmotic stimuli, presumably acting through membrane stretch, efficiently gate VR-OAC. PMID:11081638 This novel cation-selective channel is gated by exposure to hypotonicity within the physiological range. file:rat/Trpv4/Trpv4-uniprot.txt Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity |
| GO:0015275 stretch-activated, monoatomic cation-selective, calcium channel activity | ISO GO_REF:0000121 | ACCEPT | Summary: Mechanosensitive (osmotic swelling / membrane stretch) gating of the TRPV4 Ca2+-permeable cation channel. Reason: TRPV4 is gated by hypotonic cell swelling, presumably through membrane stretch, and conducts Ca2+. This descendant of calcium channel activity describes the osmo/mechanically gated mode; it is accepted alongside the general term because the channel is polymodal and the direct-stretch mechanism remains debated. Supporting Evidence: PMID:11081638 Our experiments establish that osmotic stimuli, presumably acting through membrane stretch, efficiently gate VR-OAC. PMID:11081638 This novel cation-selective channel is gated by exposure to hypotonicity within the physiological range. file:rat/Trpv4/Trpv4-uniprot.txt Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity |
| GO:0015867 ATP transport | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: ATP transport (pig ISO). Reason: TRPV4 is a Ca2+-permeable cation channel, and TRPV4-dependent (Ca2+-triggered) ATP release from cells is real, so the term is not entirely wrong as a description of the process TRPV4 activity drives. It overstates the role, though, because the ATP is released by other pathways downstream of TRPV4 Ca2+ entry rather than moved by TRPV4 itself. The pig source was not inspected, hence over-annotation rather than removal. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: FUNCTIONAL DIVERGENCE ROLE CONFLATION Sources checked: RGD:13967072 SOURCE WEAK OR INFERRED Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: Generic membrane term from InterPro mapping. Reason: Correct but general; TRPV4 is a plasma-membrane channel and the gene already carries GO:0005886. Proposed replacements: plasma membrane Supporting Evidence: PMID:11081638 Confocal microscopy of transiently and stably transfected cells indicated that both the intact and deleted fusion proteins were localized to the plasma membrane. PMID:20650893 TRPV4 was localized at the cell surface in non-stimulated cells |
| GO:0016324 apical plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Apical plasma membrane of polarized epithelia (kidney, airway). Reason: UniProt records apical cell membrane (expression in kidney tubular epithelia, PMID:11081638) and ortholog data place TRPV4 apically in epithelia. A context-specific sub-location, non-core. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Apical cell membrane |
| GO:0016324 apical plasma membrane | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Apical plasma membrane of polarized epithelia (kidney, airway). Reason: UniProt records apical cell membrane (expression in kidney tubular epithelia, PMID:11081638) and ortholog data place TRPV4 apically in epithelia. A context-specific sub-location, non-core. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Apical cell membrane |
| GO:0016324 apical plasma membrane | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Apical plasma membrane of polarized epithelia (kidney, airway). Reason: UniProt records apical cell membrane (expression in kidney tubular epithelia, PMID:11081638) and ortholog data place TRPV4 apically in epithelia. A context-specific sub-location, non-core. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Apical cell membrane |
| GO:0016324 apical plasma membrane | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Apical plasma membrane of polarized epithelia (kidney, airway). Reason: UniProt records apical cell membrane (expression in kidney tubular epithelia, PMID:11081638) and ortholog data place TRPV4 apically in epithelia. A context-specific sub-location, non-core. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Apical cell membrane |
| GO:0019901 protein kinase binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Binding to protein kinases (Src-family kinases, PKC, WNK) that regulate TRPV4. Reason: UniProt records interaction with Src family kinases (LYN, SRC, FYN, ...) by similarity; PKCepsilon associates with the rat C-terminus. Regulatory, non-core. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Interacts with MAP7 and Src family Tyr protein kinases LYN, SRC, FYN, PMID:20657843 In addition, we also detected PKCΞ΅ in the MBP-TRPV4-Ct complex, both in presence and absence of Ca2+. |
| GO:0019901 protein kinase binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Binding to protein kinases (Src-family kinases, PKC, WNK) that regulate TRPV4. Reason: UniProt records interaction with Src family kinases (LYN, SRC, FYN, ...) by similarity; PKCepsilon associates with the rat C-terminus. Regulatory, non-core. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Interacts with MAP7 and Src family Tyr protein kinases LYN, SRC, FYN, PMID:20657843 In addition, we also detected PKCΞ΅ in the MBP-TRPV4-Ct complex, both in presence and absence of Ca2+. |
| GO:0019901 protein kinase binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Binding to protein kinases (Src-family kinases, PKC, WNK) that regulate TRPV4. Reason: UniProt records interaction with Src family kinases (LYN, SRC, FYN, ...) by similarity; PKCepsilon associates with the rat C-terminus. Regulatory, non-core. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Interacts with MAP7 and Src family Tyr protein kinases LYN, SRC, FYN, PMID:20657843 In addition, we also detected PKCΞ΅ in the MBP-TRPV4-Ct complex, both in presence and absence of Ca2+. |
| GO:0030027 lamellipodium | IDA PMID:20657843 Importance of non-selective cation channel TRPV4 interaction... | KEEP AS NON CORE | Summary: Overexpressed TRPV4-GFP is enriched in lamellipodia. Reason: Live imaging of TRPV4-GFP in F11 cells; non-core location. Supporting Evidence: PMID:20657843 we performed live cell imaging by expressing TRPV4-GFP and RFP-actin in F11 cells and we observed co-localization at filopodia, at lamellipodia, and also at cortical actin-rich structures |
| GO:0030036 actin cytoskeleton organization | IDA PMID:20657843 Importance of non-selective cation channel TRPV4 interaction... | TOO GENERAL | Summary: Actin cytoskeleton organization (parent of actin filament organization). Reason: Ancestor of GO:0007015 actin filament organization asserted here. Supporting Evidence: PMID:20657843 We observed that activation of TRPV4 by 4Ξ±PDD results in rapid change of lamellipodia to filopodia and/or further elongation of filopodial structures |
| GO:0030103 vasopressin secretion | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Vasopressin (ADH) secretion, downstream of CNS osmosensing (mouse acts-upstream). Reason: TRPV4-null mice release less ADH after a hyperosmotic challenge, placing TRPV4 upstream of vasopressin secretion. Systemic, non-core. Supporting Evidence: PMID:14581612 plasma levels of antidiuretic hormone were significantly lower in trpv4-/- mice than in wild-type littermates after a hyperosmotic challenge |
| GO:0030175 filopodium | IDA PMID:20657843 Importance of non-selective cation channel TRPV4 interaction... | KEEP AS NON CORE | Summary: Overexpressed TRPV4-GFP is enriched in filopodia (tips). Reason: Live imaging of TRPV4-GFP in F11 cells; non-core location. Supporting Evidence: PMID:20657843 we performed live cell imaging by expressing TRPV4-GFP and RFP-actin in F11 cells and we observed co-localization at filopodia, at lamellipodia, and also at cortical actin-rich structures PMID:20657843 We observed that activation of TRPV4 by 4Ξ±PDD results in rapid change of lamellipodia to filopodia and/or further elongation of filopodial structures |
| GO:0030426 growth cone | IDA PMID:20657843 Importance of non-selective cation channel TRPV4 interaction... | KEEP AS NON CORE | Summary: TRPV4 in growth cones of F11 cells. Reason: Shown for expressed TRPV4-GFP; non-core. Supporting Evidence: PMID:20657843 TRPV4 localizes to growth cones when expressed in F11 cells. |
| GO:0030864 cortical actin cytoskeleton | IDA PMID:20657843 Importance of non-selective cation channel TRPV4 interaction... | KEEP AS NON CORE | Summary: TRPV4 at cortical actin-rich structures. Reason: Live imaging colocalization with cortical actin; non-core. Supporting Evidence: PMID:20657843 we performed live cell imaging by expressing TRPV4-GFP and RFP-actin in F11 cells and we observed co-localization at filopodia, at lamellipodia, and also at cortical actin-rich structures |
| GO:0031117 positive regulation of microtubule depolymerization | IDA PMID:20657843 Importance of non-selective cation channel TRPV4 interaction... | KEEP AS NON CORE | Summary: TRPV4 activation disassembles microtubules (positive regulation of depolymerization). Reason: Channel activation drives microtubule disassembly and growth-cone retraction in F11 cells and neurons. Non-core. Supporting Evidence: PMID:20657843 All these results confirm that activation of TRPV4 results in microtubules disassembly |
| GO:0032308 positive regulation of prostaglandin secretion | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Positive regulation of prostaglandin secretion (pig ISO). Reason: A downstream Ca2+-dependent secretory consequence rather than a process TRPV4 itself carries out. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: RGD:13967072 SOURCE WEAK OR INFERRED Supporting Evidence: PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells |
| GO:0032496 response to lipopolysaccharide | ISO NOT GO_REF:0000121 | KEEP AS NON CORE | Summary: TRPV4 does NOT respond to lipopolysaccharide (NOT, mouse). Reason: Negated annotation transferred from mouse; respected as a non-core negative statement. |
| GO:0032587 ruffle membrane | IDA PMID:20657843 Importance of non-selective cation channel TRPV4 interaction... | KEEP AS NON CORE | Summary: TRPV4 enriched in membrane ruffles. Reason: Immunostaining of F11 cells; non-core. Supporting Evidence: PMID:20657843 Co-localization was observed at the plasma membrane and at membrane ruffles that are enriched in TRPV4 |
| GO:0032755 positive regulation of interleukin-6 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TRPV4 promotes interleukin-6 production in adipocytes. Reason: Cell-autonomous chemokine/cytokine induction via TRPV4-ERK1/2 signalling (mouse adipocyte knockdown and agonist). Context-specific inflammatory output, non-core. Supporting Evidence: PMID:23021218 Knock-down of TRPV4 had a profound inhibitory effect on a whole array of chemokines, such as Ccl2 (Mcp1), Ccl3 (Mip1Ξ±), Ccl5 (Rantes), Ccl7 (Mcp3), Cxcl1 (KC), Ccl8, Cxcl5 and Cxcl10 and cytokines such as Il6, Saa3 and Thrombospondin (Figure 3A). PMID:23021218 These data strongly suggest that the ERK1/2 protein kinases mediate much of the effect of TRPV4 activation on both the repression of Pgc1Ξ± expression and the induction of many chemokines/cytokines in adipocytes. |
| GO:0032755 positive regulation of interleukin-6 production | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: TRPV4 promotes interleukin-6 production in adipocytes. Reason: Cell-autonomous chemokine/cytokine induction via TRPV4-ERK1/2 signalling (mouse adipocyte knockdown and agonist). Context-specific inflammatory output, non-core. Supporting Evidence: PMID:23021218 Knock-down of TRPV4 had a profound inhibitory effect on a whole array of chemokines, such as Ccl2 (Mcp1), Ccl3 (Mip1Ξ±), Ccl5 (Rantes), Ccl7 (Mcp3), Cxcl1 (KC), Ccl8, Cxcl5 and Cxcl10 and cytokines such as Il6, Saa3 and Thrombospondin (Figure 3A). PMID:23021218 These data strongly suggest that the ERK1/2 protein kinases mediate much of the effect of TRPV4 activation on both the repression of Pgc1Ξ± expression and the induction of many chemokines/cytokines in adipocytes. |
| GO:0032868 response to insulin | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: response to insulin: TRPV4-null / antagonist-treated mice are protected from diet-induced obesity and insulin resistance. Reason: Organism-level metabolic phenotypes of TRPV4 loss arise from its adipocyte signalling role; they are downstream systemic consequences, not processes TRPV4 directly participates in. Supporting Evidence: PMID:23021218 Mice with a null mutation for TRPV4 or wild-type mice treated with a TRPV4 antagonist showed elevated thermogenesis in adipose tissues and were protected from diet-induced obesity, adipose inflammation, and insulin resistance. PMID:23021218 TRPV4 negatively regulated the expression of PGC1Ξ±, UCP1, and cellular respiration. |
| GO:0032868 response to insulin | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: response to insulin: TRPV4-null / antagonist-treated mice are protected from diet-induced obesity and insulin resistance. Reason: Organism-level metabolic phenotypes of TRPV4 loss arise from its adipocyte signalling role; they are downstream systemic consequences, not processes TRPV4 directly participates in. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1926945 SOURCE WEAK OR INFERRED Supporting Evidence: PMID:23021218 Mice with a null mutation for TRPV4 or wild-type mice treated with a TRPV4 antagonist showed elevated thermogenesis in adipose tissues and were protected from diet-induced obesity, adipose inflammation, and insulin resistance. PMID:23021218 TRPV4 negatively regulated the expression of PGC1Ξ±, UCP1, and cellular respiration. |
| GO:0034605 cellular response to heat | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cellular response to heat: TRPV4 is warm-activated (mouse/human). Reason: TRPV4 orthologs mediate warm-evoked currents and Ca2+ influx (oocytes, HEK293); rat lymphatics use TRPV4 for temperature sensing. Thermosensory role, non-core (the original rat clone showed no heat response in isotonic medium). Supporting Evidence: PMID:12151520 In response to warm temperatures, TRPV4 mediates large inward currents in Xenopus oocytes and both inward currents and calcium influx into human embryonic kidney 293 cells. PMID:32706268 the selective activation of TRPV4 channels by means of GSK1016790A mirrored the behavior of vessels exposed to increasing temperatures |
| GO:0034605 cellular response to heat | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cellular response to heat: TRPV4 is warm-activated (mouse/human). Reason: TRPV4 orthologs mediate warm-evoked currents and Ca2+ influx (oocytes, HEK293); rat lymphatics use TRPV4 for temperature sensing. Thermosensory role, non-core (the original rat clone showed no heat response in isotonic medium). Supporting Evidence: PMID:12151520 In response to warm temperatures, TRPV4 mediates large inward currents in Xenopus oocytes and both inward currents and calcium influx into human embryonic kidney 293 cells. PMID:32706268 the selective activation of TRPV4 channels by means of GSK1016790A mirrored the behavior of vessels exposed to increasing temperatures |
| GO:0034605 cellular response to heat | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cellular response to heat: TRPV4 is warm-activated (mouse/human). Reason: TRPV4 orthologs mediate warm-evoked currents and Ca2+ influx (oocytes, HEK293); rat lymphatics use TRPV4 for temperature sensing. Thermosensory role, non-core (the original rat clone showed no heat response in isotonic medium). Supporting Evidence: PMID:12151520 In response to warm temperatures, TRPV4 mediates large inward currents in Xenopus oocytes and both inward currents and calcium influx into human embryonic kidney 293 cells. PMID:32706268 the selective activation of TRPV4 channels by means of GSK1016790A mirrored the behavior of vessels exposed to increasing temperatures |
| GO:0042169 SH2 domain binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SH2 domain binding: phosphotyrosine-dependent association with Src-family kinases, transferred from mouse. Reason: Consistent with Src-family kinase interaction recorded in UniProt; regulatory and peripheral. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Interacts with MAP7 and Src family Tyr protein kinases LYN, SRC, FYN, |
| GO:0042169 SH2 domain binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: SH2 domain binding: phosphotyrosine-dependent association with Src-family kinases, transferred from mouse. Reason: Consistent with Src-family kinase interaction recorded in UniProt; regulatory and peripheral. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Interacts with MAP7 and Src family Tyr protein kinases LYN, SRC, FYN, |
| GO:0042538 hyperosmotic salinity response | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Hyperosmotic salinity response (acts upstream), from mouse. Reason: TRPV4-null mice have an impaired response to a hyperosmolar (hypertonic saline) challenge (reduced drinking and ADH release); a systemic CNS osmoregulatory role, non-core. Supporting Evidence: PMID:14581612 plasma levels of antidiuretic hormone were significantly lower in trpv4-/- mice than in wild-type littermates after a hyperosmotic challenge PMID:14581612 TRPV4 is necessary for the normal response to changes in osmotic pressure and functions as an osmotic sensor in the CNS |
| GO:0042593 glucose homeostasis | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: glucose homeostasis: TRPV4-null / antagonist-treated mice are protected from diet-induced obesity and insulin resistance. Reason: Organism-level metabolic phenotypes of TRPV4 loss arise from its adipocyte signalling role; they are downstream systemic consequences, not processes TRPV4 directly participates in. Supporting Evidence: PMID:23021218 Mice with a null mutation for TRPV4 or wild-type mice treated with a TRPV4 antagonist showed elevated thermogenesis in adipose tissues and were protected from diet-induced obesity, adipose inflammation, and insulin resistance. PMID:23021218 TRPV4 negatively regulated the expression of PGC1Ξ±, UCP1, and cellular respiration. |
| GO:0042593 glucose homeostasis | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: glucose homeostasis: TRPV4-null / antagonist-treated mice are protected from diet-induced obesity and insulin resistance. Reason: Organism-level metabolic phenotypes of TRPV4 loss arise from its adipocyte signalling role; they are downstream systemic consequences, not processes TRPV4 directly participates in. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1926945 SOURCE WEAK OR INFERRED Supporting Evidence: PMID:23021218 Mice with a null mutation for TRPV4 or wild-type mice treated with a TRPV4 antagonist showed elevated thermogenesis in adipose tissues and were protected from diet-induced obesity, adipose inflammation, and insulin resistance. PMID:23021218 TRPV4 negatively regulated the expression of PGC1Ξ±, UCP1, and cellular respiration. |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Self-association: TRPV4 subunits assemble into homotetrameric channels. Reason: TRPV4 is a homotetramer; subunit self-association is required for channel assembly but the term is not itself the channel activity. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Homotetramer. file:rat/Trpv4/Trpv4-uniprot.txt Assembly of the putative homotetramer occurs primarily in the endoplasmic reticulum. |
| GO:0042802 identical protein binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Self-association: TRPV4 subunits assemble into homotetrameric channels. Reason: TRPV4 is a homotetramer; subunit self-association is required for channel assembly but the term is not itself the channel activity. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Homotetramer. file:rat/Trpv4/Trpv4-uniprot.txt Assembly of the putative homotetramer occurs primarily in the endoplasmic reticulum. |
| GO:0043014 alpha-tubulin binding | IDA PMID:20657843 Importance of non-selective cation channel TRPV4 interaction... | KEEP AS NON CORE | Summary: Binding to alpha-tubulin (alpha/beta tubulin heterodimer) by the TRPV4 C-terminus. Reason: Tubulin dimers (detected with alpha- and beta-tubulin antibodies) bind the TRPV4 C-terminus and co-immunoprecipitate with TRPV4 from rat DRG neurons. Peripheral to channel function. Supporting Evidence: PMID:20657843 The C-terminus of TRPV4 is sufficient for interaction with actin and tubulin PMID:20657843 We observed that tubulin co-immunoprecipitated with TRPV4 even from DRG neurons |
| GO:0043117 positive regulation of vascular permeability | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: TRPV4 promotes endothelial vascular permeability (lung capillary edema). Reason: TRPV4 blockade prevents the permeability increase and edema caused by high pulmonary venous pressure; a tissue-level physiological role. Supporting Evidence: PMID:23136043 TRPV4 blockade prevented the increased vascular permeability and resultant pulmonary edema associated with elevated PVP PMID:23136043 inhibits Ca(2+) influx through recombinant TRPV4 channels and native endothelial TRPV4 currents |
| GO:0043117 positive regulation of vascular permeability | IMP PMID:23136043 An orally active TRPV4 channel blocker prevents and resolves... | KEEP AS NON CORE | Summary: TRPV4 promotes endothelial vascular permeability (lung capillary edema). Reason: TRPV4 blockade prevents the permeability increase and edema caused by high pulmonary venous pressure; a tissue-level physiological role. Supporting Evidence: PMID:23136043 TRPV4 blockade prevented the increased vascular permeability and resultant pulmonary edema associated with elevated PVP PMID:23136043 inhibits Ca(2+) influx through recombinant TRPV4 channels and native endothelial TRPV4 currents |
| GO:0043117 positive regulation of vascular permeability | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: TRPV4 promotes endothelial vascular permeability (lung capillary edema). Reason: TRPV4 blockade prevents the permeability increase and edema caused by high pulmonary venous pressure; a tissue-level physiological role. Supporting Evidence: PMID:23136043 TRPV4 blockade prevented the increased vascular permeability and resultant pulmonary edema associated with elevated PVP PMID:23136043 inhibits Ca(2+) influx through recombinant TRPV4 channels and native endothelial TRPV4 currents |
| GO:0043117 positive regulation of vascular permeability | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: TRPV4 promotes endothelial vascular permeability (lung capillary edema). Reason: TRPV4 blockade prevents the permeability increase and edema caused by high pulmonary venous pressure; a tissue-level physiological role. Supporting Evidence: PMID:23136043 TRPV4 blockade prevented the increased vascular permeability and resultant pulmonary edema associated with elevated PVP PMID:23136043 inhibits Ca(2+) influx through recombinant TRPV4 channels and native endothelial TRPV4 currents |
| GO:0043117 positive regulation of vascular permeability | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: TRPV4 promotes endothelial vascular permeability (lung capillary edema). Reason: TRPV4 blockade prevents the permeability increase and edema caused by high pulmonary venous pressure; a tissue-level physiological role. Supporting Evidence: PMID:23136043 TRPV4 blockade prevented the increased vascular permeability and resultant pulmonary edema associated with elevated PVP PMID:23136043 inhibits Ca(2+) influx through recombinant TRPV4 channels and native endothelial TRPV4 currents |
| GO:0043622 cortical microtubule organization | IDA PMID:20657843 Importance of non-selective cation channel TRPV4 interaction... | KEEP AS NON CORE | Summary: TRPV4 stabilizes cortical/submembranous microtubules at the membrane. Reason: Microtubule ends extend to and are stabilized at TRPV4-containing membrane regions. Non-core. Supporting Evidence: PMID:20657843 Often these microtubule ends extended to the plasma membrane and seemed to be stabilized at the membranous regions containing TRPV4. |
| GO:0045794 negative regulation of cell volume | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Regulatory volume decrease: TRPV4 Ca2+ influx triggers RVD after swelling. Reason: In rat astrocytes TRPV4 is required for the hypotonicity-evoked Ca2+ rise and RVD; a volume-control output of the channel. Supporting Evidence: PMID:21262839 showed that TRPV4 is necessary for hypotonicity-elicited [Ca 2+ ] o influx ( Fig. 2 B β D ) and RVD ( Fig. 2 E ) |
| GO:0045989 positive regulation of striated muscle contraction | IMP PMID:32706268 TRPV4 channels' dominant role in the temperature modulation ... | KEEP AS NON CORE | Summary: TRPV4 modulates intrinsic contraction of rat diaphragmatic lymphatics with temperature. Reason: IMP from rat lymphatics (abstract only): temperature-dependent TRPV4 activation changes contraction frequency and lymph flow. Full text not available to confirm the striated-muscle term choice; kept, flagged as a question. Supporting Evidence: PMID:32706268 the selective activation of TRPV4 channels by means of GSK1016790A mirrored the behavior of vessels exposed to increasing temperatures PMID:32706268 their blockade by both the nonselective antagonist Ruthenium Red and the selective antagonist HC-067047 abolished the response of lymphatics to temperature changes |
| GO:0046330 positive regulation of JNK cascade | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TRPV4 activation phosphorylates JNK1/2 in adipocytes. Reason: Cell-autonomous JNK1/2 activation by the TRPV4 agonist (mouse adipocytes). Supporting Evidence: PMID:23021218 Addition of the TRPV4 agonist to 3T3-F442A adipocytes caused a rapid phosphorylation of both ERK1/2 and JNK1/2 at sites known to reflect activation of these kinases. |
| GO:0046330 positive regulation of JNK cascade | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: TRPV4 activation phosphorylates JNK1/2 in adipocytes. Reason: Cell-autonomous JNK1/2 activation by the TRPV4 agonist (mouse adipocytes). Supporting Evidence: PMID:23021218 Addition of the TRPV4 agonist to 3T3-F442A adipocytes caused a rapid phosphorylation of both ERK1/2 and JNK1/2 at sites known to reflect activation of these kinases. |
| GO:0046785 microtubule polymerization | IDA PMID:20657843 Importance of non-selective cation channel TRPV4 interaction... | KEEP AS NON CORE | Summary: TRPV4 C-terminus promotes/stabilizes microtubule polymerization in vitro (resting state). Reason: MBP-TRPV4-Ct co-sediments with and stabilizes polymerizing microtubules. Non-core. Supporting Evidence: PMID:20657843 We observed that MBP-TRPV4-Ct but not MBP alone co-sedimented with Taxol-stabilized polymerized microtubules PMID:20657843 This result suggests a stabilization effect of MBP-TRPV4-Ct on microtubules. |
| GO:0047484 regulation of response to osmotic stress | IMP NOT PMID:23136043 An orally active TRPV4 channel blocker prevents and resolves... | UNDECIDED | Summary: NOT regulation of response to osmotic stress (IMP, PMID:23136043). Reason: The negated IMP row (PMID:23136043) comes from a heart-failure/lung-edema study whose full text is not available, so the negative claim cannot be inspected; the vague mouse-transferred regulation term is in any case redundant with the osmosensory signaling pathway and hypotonic response terms already accepted here. Left undecided for both rows rather than asserting a vague, unverifiable regulation claim. |
| GO:0047484 regulation of response to osmotic stress | ISO GO_REF:0000121 | UNDECIDED | Summary: Regulation of response to osmotic stress (a mouse ISO acts-upstream row and a negated IMP row). Reason: The negated IMP row (PMID:23136043) comes from a heart-failure/lung-edema study whose full text is not available, so the negative claim cannot be inspected; the vague mouse-transferred regulation term is in any case redundant with the osmosensory signaling pathway and hypotonic response terms already accepted here. Left undecided for both rows rather than asserting a vague, unverifiable regulation claim. Propagation Review Root cause: UNRESOLVED Failure modes: SOURCE EVIDENCE WEAK Sources checked: MGI:MGI:1926945 UNRESOLVED |
| GO:0048487 beta-tubulin binding | IDA PMID:20657843 Importance of non-selective cation channel TRPV4 interaction... | KEEP AS NON CORE | Summary: Binding to beta-tubulin (alpha/beta tubulin heterodimer) by the TRPV4 C-terminus. Reason: As for alpha-tubulin binding: tubulin heterodimer binding to the C-terminus, shown in pull-down and DRG co-IP. Supporting Evidence: PMID:20657843 The C-terminus of TRPV4 is sufficient for interaction with actin and tubulin PMID:20657843 We observed that tubulin co-immunoprecipitated with TRPV4 even from DRG neurons |
| GO:0050729 positive regulation of inflammatory response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TRPV4 promotes the adipose inflammatory response. Reason: TRPV4 controls proinflammatory gene programs in adipocytes; knockout reduces adipose inflammation. Non-core. Supporting Evidence: PMID:23021218 Knock-down of TRPV4 had a profound inhibitory effect on a whole array of chemokines, such as Ccl2 (Mcp1), Ccl3 (Mip1Ξ±), Ccl5 (Rantes), Ccl7 (Mcp3), Cxcl1 (KC), Ccl8, Cxcl5 and Cxcl10 and cytokines such as Il6, Saa3 and Thrombospondin (Figure 3A). PMID:23021218 Mice with a null mutation for TRPV4 or wild-type mice treated with a TRPV4 antagonist showed elevated thermogenesis in adipose tissues and were protected from diet-induced obesity, adipose inflammation, and insulin resistance. |
| GO:0050729 positive regulation of inflammatory response | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: TRPV4 promotes the adipose inflammatory response. Reason: TRPV4 controls proinflammatory gene programs in adipocytes; knockout reduces adipose inflammation. Non-core. Supporting Evidence: PMID:23021218 Knock-down of TRPV4 had a profound inhibitory effect on a whole array of chemokines, such as Ccl2 (Mcp1), Ccl3 (Mip1Ξ±), Ccl5 (Rantes), Ccl7 (Mcp3), Cxcl1 (KC), Ccl8, Cxcl5 and Cxcl10 and cytokines such as Il6, Saa3 and Thrombospondin (Figure 3A). PMID:23021218 Mice with a null mutation for TRPV4 or wild-type mice treated with a TRPV4 antagonist showed elevated thermogenesis in adipose tissues and were protected from diet-induced obesity, adipose inflammation, and insulin resistance. |
| GO:0050878 regulation of body fluid levels | IEA GO_REF:0000117 | TOO GENERAL | Summary: Regulation of body fluid levels (ARBA). Reason: Ancestor of multicellular organismal-level water homeostasis (GO:0050891), which is asserted in this review. Supporting Evidence: PMID:14581612 TRPV4 is necessary for the normal response to changes in osmotic pressure and functions as an osmotic sensor in the CNS |
| GO:0050891 multicellular organismal-level water homeostasis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Systemic water homeostasis: osmoregulation and endothelial fluid balance. Reason: TRPV4 contributes to body-water balance (central osmosensing; lung endothelial fluid flux). Systemic outcome, non-core. Supporting Evidence: PMID:14581612 TRPV4 is necessary for the normal response to changes in osmotic pressure and functions as an osmotic sensor in the CNS PMID:23136043 TRPV4 blockade prevented the increased vascular permeability and resultant pulmonary edema associated with elevated PVP |
| GO:0050891 multicellular organismal-level water homeostasis | IMP PMID:23136043 An orally active TRPV4 channel blocker prevents and resolves... | KEEP AS NON CORE | Summary: Systemic water homeostasis: osmoregulation and endothelial fluid balance. Reason: TRPV4 contributes to body-water balance (central osmosensing; lung endothelial fluid flux). Systemic outcome, non-core. Supporting Evidence: PMID:14581612 TRPV4 is necessary for the normal response to changes in osmotic pressure and functions as an osmotic sensor in the CNS PMID:23136043 TRPV4 blockade prevented the increased vascular permeability and resultant pulmonary edema associated with elevated PVP |
| GO:0050891 multicellular organismal-level water homeostasis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Systemic water homeostasis: osmoregulation and endothelial fluid balance. Reason: TRPV4 contributes to body-water balance (central osmosensing; lung endothelial fluid flux). Systemic outcome, non-core. Supporting Evidence: PMID:14581612 TRPV4 is necessary for the normal response to changes in osmotic pressure and functions as an osmotic sensor in the CNS PMID:23136043 TRPV4 blockade prevented the increased vascular permeability and resultant pulmonary edema associated with elevated PVP |
| GO:0051015 actin filament binding | IDA PMID:20657843 Importance of non-selective cation channel TRPV4 interaction... | KEEP AS NON CORE | Summary: Direct binding of the TRPV4 C-terminus to actin filaments. Reason: The C-terminal fragment co-sediments with polymerized actin. Peripheral to channel function. Supporting Evidence: PMID:20657843 The C-terminus of TRPV4 is sufficient for interaction with actin and tubulin |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | MODIFY | Summary: transmembrane transport: correct for TRPV4, but a parent of calcium ion import across plasma membrane. Reason: TRPV4 conducts extracellular Ca2+ into the cytosol across the plasma membrane; GO:0098703 is an is_a descendant of GO:0055085 (transmembrane transport) and is already annotated (IBA). Proposed replacements: calcium ion import across plasma membrane Supporting Evidence: PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells |
| GO:0060087 relaxation of vascular associated smooth muscle | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Vasodilation: endothelial TRPV4 Ca2+ influx relaxes vascular smooth muscle. Reason: TRPV4 in endothelium drives Ca2+-dependent (EDHF-type) relaxation; transferred from pig, consistent with the channel role. Supporting Evidence: PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells |
| GO:0060351 cartilage development involved in endochondral bone morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cartilage development in endochondral bone morphogenesis. Reason: TRPV4 is required for normal cartilage/bone (human channelopathies; UniProt by similarity). Tissue-specific, non-core. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Required for normal development and maintenance of bone and cartilage |
| GO:0060351 cartilage development involved in endochondral bone morphogenesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cartilage development in endochondral bone morphogenesis. Reason: TRPV4 is required for normal cartilage/bone (human channelopathies; UniProt by similarity). Tissue-specific, non-core. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Required for normal development and maintenance of bone and cartilage |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TRPV4 activation rapidly phosphorylates ERK1/2 in adipocytes. Reason: Cell-autonomous: agonist-induced ERK1/2 activation depends on TRPV4 and extracellular Ca2+ (mouse adipocytes). Supporting Evidence: PMID:23021218 Addition of the TRPV4 agonist to 3T3-F442A adipocytes caused a rapid phosphorylation of both ERK1/2 and JNK1/2 at sites known to reflect activation of these kinases. PMID:23021218 These data strongly suggest that the ERK1/2 protein kinases mediate much of the effect of TRPV4 activation on both the repression of Pgc1Ξ± expression and the induction of many chemokines/cytokines in adipocytes. |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: TRPV4 activation rapidly phosphorylates ERK1/2 in adipocytes. Reason: Cell-autonomous: agonist-induced ERK1/2 activation depends on TRPV4 and extracellular Ca2+ (mouse adipocytes). Supporting Evidence: PMID:23021218 Addition of the TRPV4 agonist to 3T3-F442A adipocytes caused a rapid phosphorylation of both ERK1/2 and JNK1/2 at sites known to reflect activation of these kinases. PMID:23021218 These data strongly suggest that the ERK1/2 protein kinases mediate much of the effect of TRPV4 activation on both the repression of Pgc1Ξ± expression and the induction of many chemokines/cytokines in adipocytes. |
| GO:0070509 calcium ion import | IDA PMID:20657843 Importance of non-selective cation channel TRPV4 interaction... | MODIFY | Summary: calcium ion import: correct for TRPV4, but a parent of calcium ion import across plasma membrane. Reason: TRPV4 conducts extracellular Ca2+ into the cytosol across the plasma membrane; GO:0098703 is an is_a descendant of GO:0070509 (calcium ion import) and is already annotated (IBA). Proposed replacements: calcium ion import across plasma membrane Supporting Evidence: PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells |
| GO:0070509 calcium ion import | IEA GO_REF:0000107 | MODIFY | Summary: calcium ion import: correct for TRPV4, but a parent of calcium ion import across plasma membrane. Reason: TRPV4 conducts extracellular Ca2+ into the cytosol across the plasma membrane; GO:0098703 is an is_a descendant of GO:0070509 (calcium ion import) and is already annotated (IBA). Proposed replacements: calcium ion import across plasma membrane Supporting Evidence: PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells |
| GO:0070509 calcium ion import | ISO GO_REF:0000121 | MODIFY | Summary: calcium ion import: correct for TRPV4, but a parent of calcium ion import across plasma membrane. Reason: TRPV4 conducts extracellular Ca2+ into the cytosol across the plasma membrane; GO:0098703 is an is_a descendant of GO:0070509 (calcium ion import) and is already annotated (IBA). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1926945 SUPPORTS TRANSFER Proposed replacements: calcium ion import across plasma membrane Supporting Evidence: PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells |
| GO:0070542 response to fatty acid | ISO NOT GO_REF:0000121 | KEEP AS NON CORE | Summary: TRPV4 does NOT respond to fatty acid (NOT, mouse). Reason: Negated annotation transferred from mouse; respected as a non-core negative statement. |
| GO:0070588 calcium ion transmembrane transport | IEA GO_REF:0000107 | MODIFY | Summary: calcium ion transmembrane transport: correct for TRPV4, but a parent of calcium ion import across plasma membrane. Reason: TRPV4 conducts extracellular Ca2+ into the cytosol across the plasma membrane; GO:0098703 is an is_a descendant of GO:0070588 (calcium ion transmembrane transport) and is already annotated (IBA). Proposed replacements: calcium ion import across plasma membrane Supporting Evidence: PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells |
| GO:0070588 calcium ion transmembrane transport | IMP PMID:23136043 An orally active TRPV4 channel blocker prevents and resolves... | MODIFY | Summary: calcium ion transmembrane transport: correct for TRPV4, but a parent of calcium ion import across plasma membrane. Reason: TRPV4 conducts extracellular Ca2+ into the cytosol across the plasma membrane; GO:0098703 is an is_a descendant of GO:0070588 (calcium ion transmembrane transport) and is already annotated (IBA). Proposed replacements: calcium ion import across plasma membrane Supporting Evidence: PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells |
| GO:0070588 calcium ion transmembrane transport | ISO GO_REF:0000121 | MODIFY | Summary: calcium ion transmembrane transport: correct for TRPV4, but a parent of calcium ion import across plasma membrane. Reason: TRPV4 conducts extracellular Ca2+ into the cytosol across the plasma membrane; GO:0098703 is an is_a descendant of GO:0070588 (calcium ion transmembrane transport) and is already annotated (IBA). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: RGD:13967072 SUPPORTS TRANSFER Proposed replacements: calcium ion import across plasma membrane Supporting Evidence: PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells |
| GO:0070588 calcium ion transmembrane transport | ISO GO_REF:0000121 | MODIFY | Summary: calcium ion transmembrane transport: correct for TRPV4, but a parent of calcium ion import across plasma membrane. Reason: TRPV4 conducts extracellular Ca2+ into the cytosol across the plasma membrane; GO:0098703 is an is_a descendant of GO:0070588 (calcium ion transmembrane transport) and is already annotated (IBA). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9HBA0 SUPPORTS TRANSFER Proposed replacements: calcium ion import across plasma membrane Supporting Evidence: PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells |
| GO:0071470 cellular response to osmotic stress | IEA GO_REF:0000107 | TOO GENERAL | Summary: Cellular response to osmotic stress (parent of the hypotonic response). Reason: True but less informative than GO:0071476 cellular hypotonic response, an is_a descendant asserted in this review; the rat channel responds specifically to hypotonicity. Supporting Evidence: PMID:11081638 Upon osmotic stimulation of transfected cells, intracellular fluorescence increased significantly within seconds under hypotonic but not hypertonic conditions |
| GO:0071470 cellular response to osmotic stress | ISO GO_REF:0000121 | TOO GENERAL | Summary: Cellular response to osmotic stress (parent of the hypotonic response). Reason: True but less informative than GO:0071476 cellular hypotonic response, an is_a descendant asserted in this review; the rat channel responds specifically to hypotonicity. Supporting Evidence: PMID:11081638 Upon osmotic stimulation of transfected cells, intracellular fluorescence increased significantly within seconds under hypotonic but not hypertonic conditions |
| GO:0071470 cellular response to osmotic stress | ISS GO_REF:0000024 | TOO GENERAL | Summary: Cellular response to osmotic stress (parent of the hypotonic response). Reason: True but less informative than GO:0071476 cellular hypotonic response, an is_a descendant asserted in this review; the rat channel responds specifically to hypotonicity. Supporting Evidence: PMID:11081638 Upon osmotic stimulation of transfected cells, intracellular fluorescence increased significantly within seconds under hypotonic but not hypertonic conditions |
| GO:0071476 cellular hypotonic response | IEA GO_REF:0000120 | ACCEPT | Summary: Cellular response to decreased extracellular osmolarity: the channel opens and admits Ca2+. Reason: Core sensory response of TRPV4; shown directly for the rat clone and required for the astrocyte hypotonic Ca2+ response. Supporting Evidence: PMID:11081638 Upon osmotic stimulation of transfected cells, intracellular fluorescence increased significantly within seconds under hypotonic but not hypertonic conditions PMID:21262839 showed that TRPV4 is necessary for hypotonicity-elicited [Ca 2+ ] o influx ( Fig. 2 B β D ) and RVD ( Fig. 2 E ) PMID:11081638 These control experiments establish that Ca 2+ entry through VR-OACs is both necessary and sufficient to evoke internal Ca 2+ release |
| GO:0071476 cellular hypotonic response | ISO GO_REF:0000121 | ACCEPT | Summary: Cellular response to decreased extracellular osmolarity: the channel opens and admits Ca2+. Reason: Core sensory response of TRPV4; shown directly for the rat clone and required for the astrocyte hypotonic Ca2+ response. Supporting Evidence: PMID:11081638 Upon osmotic stimulation of transfected cells, intracellular fluorescence increased significantly within seconds under hypotonic but not hypertonic conditions PMID:21262839 showed that TRPV4 is necessary for hypotonicity-elicited [Ca 2+ ] o influx ( Fig. 2 B β D ) and RVD ( Fig. 2 E ) PMID:11081638 These control experiments establish that Ca 2+ entry through VR-OACs is both necessary and sufficient to evoke internal Ca 2+ release |
| GO:0071476 cellular hypotonic response | ISO GO_REF:0000121 | ACCEPT | Summary: Cellular response to decreased extracellular osmolarity: the channel opens and admits Ca2+. Reason: Core sensory response of TRPV4; shown directly for the rat clone and required for the astrocyte hypotonic Ca2+ response. Supporting Evidence: PMID:11081638 Upon osmotic stimulation of transfected cells, intracellular fluorescence increased significantly within seconds under hypotonic but not hypertonic conditions PMID:21262839 showed that TRPV4 is necessary for hypotonicity-elicited [Ca 2+ ] o influx ( Fig. 2 B β D ) and RVD ( Fig. 2 E ) PMID:11081638 These control experiments establish that Ca 2+ entry through VR-OACs is both necessary and sufficient to evoke internal Ca 2+ release |
| GO:0071476 cellular hypotonic response | ISO GO_REF:0000121 | ACCEPT | Summary: Cellular response to decreased extracellular osmolarity: the channel opens and admits Ca2+. Reason: Core sensory response of TRPV4; shown directly for the rat clone and required for the astrocyte hypotonic Ca2+ response. Supporting Evidence: PMID:11081638 Upon osmotic stimulation of transfected cells, intracellular fluorescence increased significantly within seconds under hypotonic but not hypertonic conditions PMID:21262839 showed that TRPV4 is necessary for hypotonicity-elicited [Ca 2+ ] o influx ( Fig. 2 B β D ) and RVD ( Fig. 2 E ) PMID:11081638 These control experiments establish that Ca 2+ entry through VR-OACs is both necessary and sufficient to evoke internal Ca 2+ release |
| GO:0071477 cellular hypotonic salinity response | IEA GO_REF:0000107 | MODIFY | Summary: Annotated as hypotonic salinity response (salt-specific), transferred electronically. Reason: The rat channel is gated by osmolarity per se and does NOT sense isotonic Na+ reduction, so the salinity-specific descendant is unsupported; generalize to GO:0071476 cellular hypotonic response. Proposed replacements: cellular hypotonic response Supporting Evidence: PMID:11081638 the channel is unlikely to sense hyponatremia PMID:11081638 Upon osmotic stimulation of transfected cells, intracellular fluorescence increased significantly within seconds under hypotonic but not hypertonic conditions |
| GO:0071477 cellular hypotonic salinity response | ISO GO_REF:0000121 | MODIFY | Summary: Annotated as hypotonic salinity response (salt-specific), transferred electronically. Reason: The rat channel is gated by osmolarity per se and does NOT sense isotonic Na+ reduction, so the salinity-specific descendant is unsupported; generalize to GO:0071476 cellular hypotonic response. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1926945 SUPPORTS SOURCE BUT NOT TARGET Proposed replacements: cellular hypotonic response Supporting Evidence: PMID:11081638 the channel is unlikely to sense hyponatremia PMID:11081638 Upon osmotic stimulation of transfected cells, intracellular fluorescence increased significantly within seconds under hypotonic but not hypertonic conditions |
| GO:0071639 positive regulation of monocyte chemotactic protein-1 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TRPV4 promotes MCP-1/CCL2 production in adipocytes. Reason: Cell-autonomous chemokine/cytokine induction via TRPV4-ERK1/2 signalling (mouse adipocyte knockdown and agonist). Context-specific inflammatory output, non-core. Supporting Evidence: PMID:23021218 Knock-down of TRPV4 had a profound inhibitory effect on a whole array of chemokines, such as Ccl2 (Mcp1), Ccl3 (Mip1Ξ±), Ccl5 (Rantes), Ccl7 (Mcp3), Cxcl1 (KC), Ccl8, Cxcl5 and Cxcl10 and cytokines such as Il6, Saa3 and Thrombospondin (Figure 3A). PMID:23021218 These data strongly suggest that the ERK1/2 protein kinases mediate much of the effect of TRPV4 activation on both the repression of Pgc1Ξ± expression and the induction of many chemokines/cytokines in adipocytes. |
| GO:0071639 positive regulation of monocyte chemotactic protein-1 production | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: TRPV4 promotes MCP-1/CCL2 production in adipocytes. Reason: Cell-autonomous chemokine/cytokine induction via TRPV4-ERK1/2 signalling (mouse adipocyte knockdown and agonist). Context-specific inflammatory output, non-core. Supporting Evidence: PMID:23021218 Knock-down of TRPV4 had a profound inhibitory effect on a whole array of chemokines, such as Ccl2 (Mcp1), Ccl3 (Mip1Ξ±), Ccl5 (Rantes), Ccl7 (Mcp3), Cxcl1 (KC), Ccl8, Cxcl5 and Cxcl10 and cytokines such as Il6, Saa3 and Thrombospondin (Figure 3A). PMID:23021218 These data strongly suggest that the ERK1/2 protein kinases mediate much of the effect of TRPV4 activation on both the repression of Pgc1Ξ± expression and the induction of many chemokines/cytokines in adipocytes. |
| GO:0071642 positive regulation of macrophage inflammatory protein 1 alpha production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TRPV4 promotes MIP-1alpha/CCL3 production in adipocytes. Reason: Cell-autonomous chemokine/cytokine induction via TRPV4-ERK1/2 signalling (mouse adipocyte knockdown and agonist). Context-specific inflammatory output, non-core. Supporting Evidence: PMID:23021218 Knock-down of TRPV4 had a profound inhibitory effect on a whole array of chemokines, such as Ccl2 (Mcp1), Ccl3 (Mip1Ξ±), Ccl5 (Rantes), Ccl7 (Mcp3), Cxcl1 (KC), Ccl8, Cxcl5 and Cxcl10 and cytokines such as Il6, Saa3 and Thrombospondin (Figure 3A). PMID:23021218 These data strongly suggest that the ERK1/2 protein kinases mediate much of the effect of TRPV4 activation on both the repression of Pgc1Ξ± expression and the induction of many chemokines/cytokines in adipocytes. |
| GO:0071642 positive regulation of macrophage inflammatory protein 1 alpha production | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: TRPV4 promotes MIP-1alpha/CCL3 production in adipocytes. Reason: Cell-autonomous chemokine/cytokine induction via TRPV4-ERK1/2 signalling (mouse adipocyte knockdown and agonist). Context-specific inflammatory output, non-core. Supporting Evidence: PMID:23021218 Knock-down of TRPV4 had a profound inhibitory effect on a whole array of chemokines, such as Ccl2 (Mcp1), Ccl3 (Mip1Ξ±), Ccl5 (Rantes), Ccl7 (Mcp3), Cxcl1 (KC), Ccl8, Cxcl5 and Cxcl10 and cytokines such as Il6, Saa3 and Thrombospondin (Figure 3A). PMID:23021218 These data strongly suggest that the ERK1/2 protein kinases mediate much of the effect of TRPV4 activation on both the repression of Pgc1Ξ± expression and the induction of many chemokines/cytokines in adipocytes. |
| GO:0071651 positive regulation of chemokine (C-C motif) ligand 5 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TRPV4 promotes CCL5/RANTES production in adipocytes. Reason: Cell-autonomous chemokine/cytokine induction via TRPV4-ERK1/2 signalling (mouse adipocyte knockdown and agonist). Context-specific inflammatory output, non-core. Supporting Evidence: PMID:23021218 Knock-down of TRPV4 had a profound inhibitory effect on a whole array of chemokines, such as Ccl2 (Mcp1), Ccl3 (Mip1Ξ±), Ccl5 (Rantes), Ccl7 (Mcp3), Cxcl1 (KC), Ccl8, Cxcl5 and Cxcl10 and cytokines such as Il6, Saa3 and Thrombospondin (Figure 3A). PMID:23021218 These data strongly suggest that the ERK1/2 protein kinases mediate much of the effect of TRPV4 activation on both the repression of Pgc1Ξ± expression and the induction of many chemokines/cytokines in adipocytes. |
| GO:0071651 positive regulation of chemokine (C-C motif) ligand 5 production | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: TRPV4 promotes CCL5/RANTES production in adipocytes. Reason: Cell-autonomous chemokine/cytokine induction via TRPV4-ERK1/2 signalling (mouse adipocyte knockdown and agonist). Context-specific inflammatory output, non-core. Supporting Evidence: PMID:23021218 Knock-down of TRPV4 had a profound inhibitory effect on a whole array of chemokines, such as Ccl2 (Mcp1), Ccl3 (Mip1Ξ±), Ccl5 (Rantes), Ccl7 (Mcp3), Cxcl1 (KC), Ccl8, Cxcl5 and Cxcl10 and cytokines such as Il6, Saa3 and Thrombospondin (Figure 3A). PMID:23021218 These data strongly suggest that the ERK1/2 protein kinases mediate much of the effect of TRPV4 activation on both the repression of Pgc1Ξ± expression and the induction of many chemokines/cytokines in adipocytes. |
| GO:0090316 positive regulation of intracellular protein transport | ISO GO_REF:0000121 | UNDECIDED | Summary: Positive regulation of intracellular protein transport (pig ISO). Reason: No accessible evidence for this specific role in rat; cannot verify or refute. Propagation Review Root cause: UNRESOLVED Failure modes: SOURCE EVIDENCE WEAK Sources checked: RGD:13967072 UNRESOLVED |
| GO:0097009 energy homeostasis | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: energy homeostasis: TRPV4-null / antagonist-treated mice are protected from diet-induced obesity and insulin resistance. Reason: Organism-level metabolic phenotypes of TRPV4 loss arise from its adipocyte signalling role; they are downstream systemic consequences, not processes TRPV4 directly participates in. Supporting Evidence: PMID:23021218 Mice with a null mutation for TRPV4 or wild-type mice treated with a TRPV4 antagonist showed elevated thermogenesis in adipose tissues and were protected from diet-induced obesity, adipose inflammation, and insulin resistance. PMID:23021218 TRPV4 negatively regulated the expression of PGC1Ξ±, UCP1, and cellular respiration. |
| GO:0097009 energy homeostasis | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: energy homeostasis: TRPV4-null / antagonist-treated mice are protected from diet-induced obesity and insulin resistance. Reason: Organism-level metabolic phenotypes of TRPV4 loss arise from its adipocyte signalling role; they are downstream systemic consequences, not processes TRPV4 directly participates in. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1926945 SOURCE WEAK OR INFERRED Supporting Evidence: PMID:23021218 Mice with a null mutation for TRPV4 or wild-type mice treated with a TRPV4 antagonist showed elevated thermogenesis in adipose tissues and were protected from diet-induced obesity, adipose inflammation, and insulin resistance. PMID:23021218 TRPV4 negatively regulated the expression of PGC1Ξ±, UCP1, and cellular respiration. |
| GO:0097497 blood vessel endothelial cell delamination | IEA GO_REF:0000107 | UNDECIDED | Summary: Blood vessel endothelial cell delamination (human ISO, electronic). Reason: No accessible experimental evidence for this specific developmental role; cannot verify or refute from available sources. |
| GO:0097497 blood vessel endothelial cell delamination | ISO GO_REF:0000121 | UNDECIDED | Summary: Blood vessel endothelial cell delamination (human ISO, electronic). Reason: No accessible experimental evidence for this specific developmental role; cannot verify or refute from available sources. Propagation Review Root cause: UNRESOLVED Failure modes: SOURCE EVIDENCE WEAK Sources checked: UniProtKB:Q9HBA0 UNRESOLVED |
| GO:0098703 calcium ion import across plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Ca2+ entry from the extracellular space across the plasma membrane through TRPV4. Reason: Most specific transport term in this set; rat TRPV4 Ca2+ signals require extracellular Ca2+ and are evoked by hypotonicity or 4alpha-PDD. Supporting Evidence: PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. PMID:11081638 These control experiments establish that Ca 2+ entry through VR-OACs is both necessary and sufficient to evoke internal Ca 2+ release PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells PMID:21262839 showed that TRPV4 is necessary for hypotonicity-elicited [Ca 2+ ] o influx ( Fig. 2 B β D ) and RVD ( Fig. 2 E ) |
| GO:0098703 calcium ion import across plasma membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Ca2+ entry from the extracellular space across the plasma membrane through TRPV4. Reason: Most specific transport term in this set; rat TRPV4 Ca2+ signals require extracellular Ca2+ and are evoked by hypotonicity or 4alpha-PDD. Supporting Evidence: PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. PMID:11081638 These control experiments establish that Ca 2+ entry through VR-OACs is both necessary and sufficient to evoke internal Ca 2+ release PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells PMID:21262839 showed that TRPV4 is necessary for hypotonicity-elicited [Ca 2+ ] o influx ( Fig. 2 B β D ) and RVD ( Fig. 2 E ) |
| GO:1900744 regulation of p38MAPK cascade | ISO NOT GO_REF:0000121 | KEEP AS NON CORE | Summary: TRPV4 does NOT activate the p38 MAPK cascade (NOT, mouse). Reason: Negated annotation supported directly: the TRPV4 agonist caused no activating p38 phosphorylation in adipocytes. Supporting Evidence: PMID:23021218 In contrast, no activating phosphorylation on p38 MAPK was detected with TRPV4 agonism |
| GO:1902632 positive regulation of membrane hyperpolarization | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of membrane hyperpolarization (pig ISO). Reason: TRPV4 Ca2+ influx activates Ca2+-activated K+ channels in endothelium, hyperpolarizing the membrane; plausible downstream role. Supporting Evidence: PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells |
| GO:1902656 calcium ion import into cytosol | IEA GO_REF:0000107 | MODIFY | Summary: calcium ion import into cytosol: correct for TRPV4, but a parent of calcium ion import across plasma membrane. Reason: TRPV4 conducts extracellular Ca2+ into the cytosol across the plasma membrane; GO:0098703 is an is_a descendant of GO:1902656 (calcium ion import into cytosol) and is already annotated (IBA). Proposed replacements: calcium ion import across plasma membrane Supporting Evidence: PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells |
| GO:1902656 calcium ion import into cytosol | ISO GO_REF:0000121 | MODIFY | Summary: calcium ion import into cytosol: correct for TRPV4, but a parent of calcium ion import across plasma membrane. Reason: TRPV4 conducts extracellular Ca2+ into the cytosol across the plasma membrane; GO:0098703 is an is_a descendant of GO:1902656 (calcium ion import into cytosol) and is already annotated (IBA). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9HBA0 SUPPORTS TRANSFER Proposed replacements: calcium ion import across plasma membrane Supporting Evidence: PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells |
| GO:1902656 calcium ion import into cytosol | ISS GO_REF:0000024 | MODIFY | Summary: calcium ion import into cytosol: correct for TRPV4, but a parent of calcium ion import across plasma membrane. Reason: TRPV4 conducts extracellular Ca2+ into the cytosol across the plasma membrane; GO:0098703 is an is_a descendant of GO:1902656 (calcium ion import into cytosol) and is already annotated (IBA). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9HBA0 SUPPORTS TRANSFER Proposed replacements: calcium ion import across plasma membrane Supporting Evidence: PMID:11081638 No change in fluorescence was apparent upon substitution of hypotonic solution lacking Ca 2+ ; subsequent addition of 2 mM Ca 2+ led within a few seconds to a strong increase of intracellular fluorescence. PMID:20650893 4-Ξ±-PDD stimulation resulted in a strong Ca2+ influx, as expected, in PBS-treated cells |
| GO:1903444 negative regulation of brown fat cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TRPV4 restrains the adipocyte browning/thermogenic program. Reason: Cell-autonomous: adipocytes from Trpv4-null mice upregulate the browning gene program. Non-core regulatory role. Supporting Evidence: PMID:23021218 TRPV4 negatively regulated the expression of PGC1Ξ±, UCP1, and cellular respiration. PMID:23021218 Mice with a null mutation for TRPV4 or wild-type mice treated with a TRPV4 antagonist showed elevated thermogenesis in adipose tissues and were protected from diet-induced obesity, adipose inflammation, and insulin resistance. |
| GO:1903444 negative regulation of brown fat cell differentiation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: TRPV4 restrains the adipocyte browning/thermogenic program. Reason: Cell-autonomous: adipocytes from Trpv4-null mice upregulate the browning gene program. Non-core regulatory role. Supporting Evidence: PMID:23021218 TRPV4 negatively regulated the expression of PGC1Ξ±, UCP1, and cellular respiration. PMID:23021218 Mice with a null mutation for TRPV4 or wild-type mice treated with a TRPV4 antagonist showed elevated thermogenesis in adipose tissues and were protected from diet-induced obesity, adipose inflammation, and insulin resistance. |
| GO:1903715 regulation of aerobic respiration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TRPV4 negatively regulates adipocyte cellular respiration. Reason: TRPV4 negatively regulates Pgc1a/Ucp1 and cellular respiration in adipocytes (cell-autonomous). Non-core. Supporting Evidence: PMID:23021218 TRPV4 negatively regulated the expression of PGC1Ξ±, UCP1, and cellular respiration. |
| GO:1903715 regulation of aerobic respiration | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: TRPV4 negatively regulates adipocyte cellular respiration. Reason: TRPV4 negatively regulates Pgc1a/Ucp1 and cellular respiration in adipocytes (cell-autonomous). Non-core. Supporting Evidence: PMID:23021218 TRPV4 negatively regulated the expression of PGC1Ξ±, UCP1, and cellular respiration. |
| GO:1904669 ATP export | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: ATP export (pig ISO). Reason: TRPV4 is a Ca2+-permeable cation channel, and TRPV4-dependent (Ca2+-triggered) ATP release from cells is real, so the term is not entirely wrong as a description of the process TRPV4 activity drives. It overstates the role, though, because the ATP is released by other pathways downstream of TRPV4 Ca2+ entry rather than moved by TRPV4 itself. The pig source was not inspected, hence over-annotation rather than removal. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: FUNCTIONAL DIVERGENCE ROLE CONFLATION Sources checked: RGD:13967072 SOURCE WEAK OR INFERRED Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity |
| GO:1990079 cartilage homeostasis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cartilage homeostasis (pig ISO). Reason: Consistent with the chondrocyte role recorded by UniProt. Non-core. Supporting Evidence: file:rat/Trpv4/Trpv4-uniprot.txt Required for normal development and maintenance of bone and cartilage |
| GO:2000340 positive regulation of chemokine (C-X-C motif) ligand 1 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TRPV4 promotes CXCL1 production in adipocytes. Reason: Cell-autonomous chemokine/cytokine induction via TRPV4-ERK1/2 signalling (mouse adipocyte knockdown and agonist). Context-specific inflammatory output, non-core. Supporting Evidence: PMID:23021218 Knock-down of TRPV4 had a profound inhibitory effect on a whole array of chemokines, such as Ccl2 (Mcp1), Ccl3 (Mip1Ξ±), Ccl5 (Rantes), Ccl7 (Mcp3), Cxcl1 (KC), Ccl8, Cxcl5 and Cxcl10 and cytokines such as Il6, Saa3 and Thrombospondin (Figure 3A). PMID:23021218 These data strongly suggest that the ERK1/2 protein kinases mediate much of the effect of TRPV4 activation on both the repression of Pgc1Ξ± expression and the induction of many chemokines/cytokines in adipocytes. |
| GO:2000340 positive regulation of chemokine (C-X-C motif) ligand 1 production | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: TRPV4 promotes CXCL1 production in adipocytes. Reason: Cell-autonomous chemokine/cytokine induction via TRPV4-ERK1/2 signalling (mouse adipocyte knockdown and agonist). Context-specific inflammatory output, non-core. Supporting Evidence: PMID:23021218 Knock-down of TRPV4 had a profound inhibitory effect on a whole array of chemokines, such as Ccl2 (Mcp1), Ccl3 (Mip1Ξ±), Ccl5 (Rantes), Ccl7 (Mcp3), Cxcl1 (KC), Ccl8, Cxcl5 and Cxcl10 and cytokines such as Il6, Saa3 and Thrombospondin (Figure 3A). PMID:23021218 These data strongly suggest that the ERK1/2 protein kinases mediate much of the effect of TRPV4 activation on both the repression of Pgc1Ξ± expression and the induction of many chemokines/cytokines in adipocytes. |
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Download this section (compressed HTML)Q: Is rat TRPV4 directly gated by membrane stretch, or does swelling activate it indirectly through aquaporin-4-mediated water flux and the actin cytoskeleton?
Q: Does the GO:0045989 (positive regulation of striated muscle contraction) annotation from rat diaphragmatic lymphatics (PMID:32706268) use the correct muscle-type term, given that lymphatic vessel wall muscle is generally smooth muscle?
Q: Do the NOT annotations for regulation of heart rate and blood pressure (PMID:23136043) hold, and what is the direct cardiovascular readout, given that systemic TRPV4 activation can cause circulatory collapse?
Experiment: Patch-clamp of rat TRPV4 in excised, cytoskeleton-free membrane patches with calibrated pressure steps to test direct mechanical gating independent of AQP4.
Experiment: Cell-type-specific (endothelial vs neuronal) conditional Trpv4 knockout in rat to separate the lung vascular-permeability role from the CNS osmoregulatory role in vivo.
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