Atp2a2 encodes SERCA2, the sarco/endoplasmic reticulum Ca2+-ATPase 2, a P-type (type IIA) ion pump with ten transmembrane helices that couples the hydrolysis of ATP, via a phosphorylated aspartate intermediate, to the transport of Ca2+ from the cytosol into the lumen of the endoplasmic and sarcoplasmic reticulum. Alternative splicing gives SERCA2b, the ubiquitous housekeeping ER Ca2+ pump that maintains the ER Ca2+ store in all cells, and SERCA2a, the isoform of heart and slow-twitch skeletal muscle. In cardiomyocytes SERCA2a re-sequesters Ca2+ released during each beat, so its activity sets the rate of relaxation and the SR Ca2+ load available for the next contraction. Activity is regulated by the transmembrane micropeptide phospholamban, whose inhibition is relieved by PKA phosphorylation within an AKAP18delta signalling complex, and by sarcolipin, S100A1, oxidative modifications and other partners. SERCA2 expression is induced by ER stress through ATF6 and repressed by inflammatory NF-kB signalling. Beyond store loading, SERCA2 activity, promoted by VMP1, helps resolve ER-isolation membrane contacts during autophagosome formation, and SERCA2b associates with nascent G protein-coupled receptors during their biogenesis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000045 autophagosome assembly | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA for autophagosome assembly from the PAINT node shared with human SERCA2. Reason: Human SERCA2 (P16615) is the donor. In mammalian cells VMP1 binds SERCA, keeps PLN/SLN off it and so promotes its Ca2+-pump activity, which controls the dissociation of ER-isolation membrane contacts during autophagosome formation (PMID:28890335). SERCA2 therefore contributes its pump activity to a step of autophagosome biogenesis, but this is a regulatory, context-specific role beside its housekeeping Ca2+-loading function; kept as non-core. The IBA node is seeded by human P16615 (UniProt IDA, PMID:28890335); rat Atp2a2 lies inside that clade with no evidence of divergence. Supporting Evidence: PMID:28890335 VMP1 controls contact formation by promoting SERCA PMID:28890335 During autophagosome formation in mammalian cells, isolation membranes (IMs; autophagosome precursors) dynamically contact the ER. |
| GO:0000045 autophagosome assembly | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO for autophagosome assembly from human SERCA2. Reason: Human SERCA2 (P16615) is the donor. In mammalian cells VMP1 binds SERCA, keeps PLN/SLN off it and so promotes its Ca2+-pump activity, which controls the dissociation of ER-isolation membrane contacts during autophagosome formation (PMID:28890335). SERCA2 therefore contributes its pump activity to a step of autophagosome biogenesis, but this is a regulatory, context-specific role beside its housekeeping Ca2+-loading function; kept as non-core. Supporting Evidence: PMID:28890335 VMP1 controls contact formation by promoting SERCA PMID:28890335 During autophagosome formation in mammalian cells, isolation membranes (IMs; autophagosome precursors) dynamically contact the ER. |
| GO:0000045 autophagosome assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS for autophagosome assembly from human SERCA2. Reason: Human SERCA2 (P16615) is the donor. In mammalian cells VMP1 binds SERCA, keeps PLN/SLN off it and so promotes its Ca2+-pump activity, which controls the dissociation of ER-isolation membrane contacts during autophagosome formation (PMID:28890335). SERCA2 therefore contributes its pump activity to a step of autophagosome biogenesis, but this is a regulatory, context-specific role beside its housekeeping Ca2+-loading function; kept as non-core. Supporting Evidence: PMID:28890335 VMP1 controls contact formation by promoting SERCA PMID:28890335 During autophagosome formation in mammalian cells, isolation membranes (IMs; autophagosome precursors) dynamically contact the ER. |
| GO:0000166 nucleotide binding | IEA GO_REF:0000002 | MODIFY | Summary: InterPro-based nucleotide binding (P-type ATPase cytoplasmic N domain). Reason: True but general. The nucleotide bound by the SERCA N-domain is ATP, which phosphorylates the active-site Asp in each catalytic cycle; GO:0005524 ATP binding (a descendant, already carried by this gene) is the supported term. Proposed replacements: ATP binding Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Ca(2+) binding to the cytosolic domain of the pump in the high-affinity E1 conformation is followed by the ATP-dependent phosphorylation of the active site Asp PMID:12409282 competitive inhibitors of the nucleotide-binding and Ca(2+)-binding sites on the enzyme, respectively |
| GO:0002026 regulation of the force of heart contraction | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO (mouse IGI, PMID:10555147) for regulation of the force of heart contraction. Reason: SERCA2a sets SR Ca2+ load and hence the amplitude of the Ca2+ transient and contractile force; SERCA2a overexpression increased contractility in mouse hearts (PMID:9851937). The effect on force follows from its pump activity, so this is a true but physiological, non-core consequence. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:88110 · Atp2a2 mouse SUPPORTS TRANSFER Mouse PLN/SERCA2a genetic interaction in dilated cardiomyopathy model (PMID:10555147); SERCA2a activity sets contractile force. Supporting Evidence: PMID:9851937 The present study demonstrates that increases in SERCA2a pump levels can directly enhance contractile function of the heart by increasing SR Ca2+ transport. PMID:10555147 The ablation of a muscle-specific sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) inhibitor, phospholamban, rescued the spectrum of phenotypes that resemble human heart failure. |
| GO:0005246 calcium channel regulator activity | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: ISO from human SERCA2 (ARUK-UCL IMP, PMID:18068335, platelet store-operated Ca2+ entry). Reason: The donor study shows that SERCA2b/3 activity influences store-operated Ca2+ entry in human platelets. SERCA2 influences SOCE by filling or emptying the ER store that STIM senses, i.e. through its pump activity, not by acting as a regulator of a calcium channel. Calling this calcium channel regulator activity is an over-interpretation of an indirect effect; not transferred as an MF to rat. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P16615 · ATP2A2 human SOURCE WEAK OR INFERRED Human IMP (PMID:18068335) reads an indirect store-depletion effect on SOCE as channel-regulator activity. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. PMID:18068335 which reveals a negative role for SERCAs in the regulation of SOCE |
| GO:0005388 P-type calcium transporter activity | IDA PMID:12409282 Mechanisms underlying increases in SR Ca2+-ATPase activity a... | ACCEPT | Summary: IDA, rat skeletal muscle SR vesicle Ca2+-ATPase Vmax and Ca2+ uptake after exercise (abstract only). Reason: SERCA2 is the P-type type IIA Ca2+-ATPase that couples ATP hydrolysis to Ca2+ translocation from the cytosol into the ER/SR lumen; this is its defining core activity. The vesicles are from fast gastrocnemius, where SERCA1 dominates, so the assay is not SERCA2-specific, but the activity is unequivocally correct for SERCA2 and the RGD curator read the full text; accepted. Supporting Evidence: PMID:12409282 both V(max) and Ca(2+) uptake were higher PMID:21300842 Total ventricular SERCA2a protein remained unchanged, but its ability to hydrolyze ATP and transport Ca(2+) was significantly reduced. file:rat/Atp2a2/Atp2a2-deep-research-manual.md These vesicles come from fast gastrocnemius, where SERCA1 dominates, so the assay is not SERCA2-specific. |
| GO:0005388 P-type calcium transporter activity | IDA PMID:21300842 Carbonylation contributes to SERCA2a activity loss and diast... | ACCEPT | Summary: IDA, rat heart SERCA2a ATP hydrolysis and Ca2+ transport assays (full text read). Reason: SERCA2 is the P-type type IIA Ca2+-ATPase that couples ATP hydrolysis to Ca2+ translocation from the cytosol into the ER/SR lumen; this is its defining core activity. This paper measures thapsigargin-sensitive Ca2+ uptake and Ca2+-ATPase activity of rat cardiac SERCA2a and of recombinant wild-type and mutant SERCA2a. Supporting Evidence: PMID:21300842 Total ventricular SERCA2a protein remained unchanged, but its ability to hydrolyze ATP and transport Ca(2+) was significantly reduced. PMID:21300842 the ATP-driven pump that translocates Ca(2+) from the cytoplasm to the lumen of the sarcoplasmic reticulum |
| GO:0005388 P-type calcium transporter activity | IDA PMID:9851937 Targeted overexpression of the sarcoplasmic reticulum Ca2+-A... | ACCEPT | Summary: IDA, SERCA2a overexpression raises SR Ca2+ uptake Vmax (abstract). Reason: SERCA2 is the P-type type IIA Ca2+-ATPase that couples ATP hydrolysis to Ca2+ translocation from the cytosol into the ER/SR lumen; this is its defining core activity. Supporting Evidence: PMID:9851937 The maximum velocity of Ca2+ uptake (Vmax) was increased by 37%, demonstrating that increased pump levels result in increased SR Ca2+ uptake function. |
| GO:0005388 P-type calcium transporter activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA from InterPro/EC/Rhea mapping (EC 7.2.2.10). Reason: SERCA2 is the P-type type IIA Ca2+-ATPase that couples ATP hydrolysis to Ca2+ translocation from the cytosol into the ER/SR lumen; this is its defining core activity. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IIA subfamily. file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. |
| GO:0005388 P-type calcium transporter activity | ISO GO_REF:0000121 | ACCEPT | Summary: ISO for P-type calcium transporter activity from a SERCA2 ortholog. Reason: SERCA2 is the P-type type IIA Ca2+-ATPase that couples ATP hydrolysis to Ca2+ translocation from the cytosol into the ER/SR lumen; this is its defining core activity. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. PMID:21300842 Total ventricular SERCA2a protein remained unchanged, but its ability to hydrolyze ATP and transport Ca(2+) was significantly reduced. |
| GO:0005388 P-type calcium transporter activity | ISO GO_REF:0000121 | ACCEPT | Summary: ISO for P-type calcium transporter activity from a SERCA2 ortholog. Reason: SERCA2 is the P-type type IIA Ca2+-ATPase that couples ATP hydrolysis to Ca2+ translocation from the cytosol into the ER/SR lumen; this is its defining core activity. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. PMID:21300842 Total ventricular SERCA2a protein remained unchanged, but its ability to hydrolyze ATP and transport Ca(2+) was significantly reduced. |
| GO:0005388 P-type calcium transporter activity | ISO GO_REF:0000121 | ACCEPT | Summary: ISO for P-type calcium transporter activity from a SERCA2 ortholog. Reason: SERCA2 is the P-type type IIA Ca2+-ATPase that couples ATP hydrolysis to Ca2+ translocation from the cytosol into the ER/SR lumen; this is its defining core activity. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. PMID:21300842 Total ventricular SERCA2a protein remained unchanged, but its ability to hydrolyze ATP and transport Ca(2+) was significantly reduced. |
| GO:0005388 P-type calcium transporter activity | ISO GO_REF:0000121 | ACCEPT | Summary: ISO for P-type calcium transporter activity from a SERCA2 ortholog. Reason: SERCA2 is the P-type type IIA Ca2+-ATPase that couples ATP hydrolysis to Ca2+ translocation from the cytosol into the ER/SR lumen; this is its defining core activity. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. PMID:21300842 Total ventricular SERCA2a protein remained unchanged, but its ability to hydrolyze ATP and transport Ca(2+) was significantly reduced. |
| GO:0005388 P-type calcium transporter activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from human SERCA2. Reason: SERCA2 is the P-type type IIA Ca2+-ATPase that couples ATP hydrolysis to Ca2+ translocation from the cytosol into the ER/SR lumen; this is its defining core activity. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. PMID:21300842 Total ventricular SERCA2a protein remained unchanged, but its ability to hydrolyze ATP and transport Ca(2+) was significantly reduced. |
| GO:0005509 calcium ion binding | IDA PMID:12409282 Mechanisms underlying increases in SR Ca2+-ATPase activity a... | KEEP AS NON CORE | Summary: IDA, NCD-4 probe of the Ca2+-binding site in rat SR vesicles (abstract only). Reason: SERCA2 binds two Ca2+ ions in its transmembrane transport sites in the E1 state; this binding is the substrate-binding step of the pump cycle and is captured by P-type calcium transporter activity. True, non-core. Supporting Evidence: PMID:12409282 competitive inhibitors of the nucleotide-binding and Ca(2+)-binding sites on the enzyme, respectively file:rat/Atp2a2/Atp2a2-uniprot.txt Ca(2+) binding to the cytosolic domain of the pump in the high-affinity E1 conformation is followed by the ATP-dependent phosphorylation of the active site Asp |
| GO:0005509 calcium ion binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA (ARBA) calcium ion binding. Reason: SERCA2 binds two Ca2+ ions in its transmembrane transport sites in the E1 state; this binding is the substrate-binding step of the pump cycle and is captured by P-type calcium transporter activity. True, non-core. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Ca(2+) binding to the cytosolic domain of the pump in the high-affinity E1 conformation is followed by the ATP-dependent phosphorylation of the active site Asp |
| GO:0005509 calcium ion binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO calcium ion binding from mouse. Reason: SERCA2 binds two Ca2+ ions in its transmembrane transport sites in the E1 state; this binding is the substrate-binding step of the pump cycle and is captured by P-type calcium transporter activity. True, non-core. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Ca(2+) binding to the cytosolic domain of the pump in the high-affinity E1 conformation is followed by the ATP-dependent phosphorylation of the active site Asp |
| GO:0005509 calcium ion binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO calcium ion binding from human. Reason: SERCA2 binds two Ca2+ ions in its transmembrane transport sites in the E1 state; this binding is the substrate-binding step of the pump cycle and is captured by P-type calcium transporter activity. True, non-core. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Ca(2+) binding to the cytosolic domain of the pump in the high-affinity E1 conformation is followed by the ATP-dependent phosphorylation of the active site Asp |
| GO:0005515 protein binding | IPI PMID:24610369 Toll-like receptor 9 protects non-immune cells from stress b... | REMOVE | Summary: IPI with TLR9 (Q9EQU3) by co-immunoprecipitation in cardiomyocytes (full text read). Reason: Bare protein binding is uninformative and is removed under the protein-binding policy. The interaction itself is real: TLR9 co-immunoprecipitates with SERCA2 and TLR9 stimulation reduces SERCA2 activity (PMID:24610369), but it describes regulation of SERCA2 by TLR9, not a binding function of SERCA2 that a more specific MF term captures. Supporting Evidence: PMID:24610369 TLR9 stimulation reduces SERCA2 activity, modulating Ca(2+) handling between the SR/ER and mitochondria |
| GO:0005524 ATP binding | IDA PMID:12409282 Mechanisms underlying increases in SR Ca2+-ATPase activity a... | KEEP AS NON CORE | Summary: IDA, FITC probe of the nucleotide-binding site in rat SR vesicles (abstract only). Reason: ATP binds the SERCA N-domain and phosphorylates the active-site Asp each cycle; ATP binding is a component of the pump mechanism. True, kept as non-core beside the transporter activity. Supporting Evidence: PMID:12409282 competitive inhibitors of the nucleotide-binding and Ca(2+)-binding sites on the enzyme, respectively file:rat/Atp2a2/Atp2a2-uniprot.txt Ca(2+) binding to the cytosolic domain of the pump in the high-affinity E1 conformation is followed by the ATP-dependent phosphorylation of the active site Asp |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: IEA (InterPro P-type ATPase) ATP binding. Reason: ATP binds the SERCA N-domain and phosphorylates the active-site Asp each cycle; ATP binding is a component of the pump mechanism. True, kept as non-core beside the transporter activity. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Ca(2+) binding to the cytosolic domain of the pump in the high-affinity E1 conformation is followed by the ATP-dependent phosphorylation of the active site Asp |
| GO:0005783 endoplasmic reticulum | ISO GO_REF:0000121 | ACCEPT | Summary: ISO endoplasmic reticulum from mouse. Reason: Root organelle term. SERCA2 is a multi-pass ER membrane protein (SERCA2b is the housekeeping ER pump of all cells), so the organelle claim holds; the ER membrane sub-compartment is already carried by this gene. Checked: donor is mouse Atp2a2 location data. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein PMID:10748035 The sarco/endoplasmic reticulum calcium-ATPase (SERCA) translocates Ca(2+) from the cytosol to the lumen of the endoplasmic reticulum. |
| GO:0005783 endoplasmic reticulum | ISO GO_REF:0000121 | ACCEPT | Summary: ISO endoplasmic reticulum from human. Reason: Root organelle term. SERCA2 is a multi-pass ER membrane protein (SERCA2b is the housekeeping ER pump of all cells), so the organelle claim holds; the ER membrane sub-compartment is already carried by this gene. Checked: donor is human ATP2A2 location data. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein PMID:10748035 The sarco/endoplasmic reticulum calcium-ATPase (SERCA) translocates Ca(2+) from the cytosol to the lumen of the endoplasmic reticulum. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA from UniProt subcellular location. Reason: SERCA2 is an integral multi-pass protein of the ER membrane where it pumps Ca2+ into the lumen; core location. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein |
| GO:0005789 endoplasmic reticulum membrane | ISO GO_REF:0000121 | ACCEPT | Summary: ISO ER membrane (is_active_in) from mouse. Reason: SERCA2 is an integral multi-pass protein of the ER membrane where it pumps Ca2+ into the lumen; core location. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein PMID:10748035 The sarco/endoplasmic reticulum calcium-ATPase (SERCA) translocates Ca(2+) from the cytosol to the lumen of the endoplasmic reticulum. |
| GO:0005789 endoplasmic reticulum membrane | ISO GO_REF:0000121 | ACCEPT | Summary: ISO ER membrane from mouse. Reason: SERCA2 is an integral multi-pass protein of the ER membrane where it pumps Ca2+ into the lumen; core location. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein |
| GO:0005789 endoplasmic reticulum membrane | ISO GO_REF:0000121 | ACCEPT | Summary: ISO ER membrane from human. Reason: SERCA2 is an integral multi-pass protein of the ER membrane where it pumps Ca2+ into the lumen; core location. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein |
| GO:0005789 endoplasmic reticulum membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ISS ER membrane from mouse. Reason: SERCA2 is an integral multi-pass protein of the ER membrane where it pumps Ca2+ into the lumen; core location. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein |
| GO:0006816 calcium ion transport | IDA PMID:11595740 Sarco/endoplasmic reticulum calcium ATPase-2 expression is r... | MODIFY | Summary: IDA from an ATF6/SERCA2 promoter study (abstract only). Reason: True but general. SERCA2 moves Ca2+ from the cytosol into the ER/SR lumen; the specific process terms GO:1903515 and GO:1990036 (both carried by this gene) state the direction and compartment. The abstract is about ATF6 control of SERCA2 expression, but it describes SERCA2 as transporting Ca2+ into the SR, so the essence (calcium transport) is sound; refine rather than remove. Proposed replacements: calcium ion transport from cytosol to endoplasmic reticulum calcium ion import into sarcoplasmic reticulum Supporting Evidence: PMID:11595740 sarco/endoplasmic reticulum calcium ATPase-2 (SERCA2), a protein that transports calcium into the SR from the cytoplasm. |
| GO:0006816 calcium ion transport | IEA GO_REF:0000002 | MODIFY | Summary: IEA (InterPro P-type ATPase IIA) calcium ion transport. Reason: True but general. SERCA2 moves Ca2+ from the cytosol into the ER/SR lumen; the specific process terms GO:1903515 and GO:1990036 (both carried by this gene) state the direction and compartment. Proposed replacements: calcium ion transport from cytosol to endoplasmic reticulum calcium ion import into sarcoplasmic reticulum Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. |
| GO:0006874 intracellular calcium ion homeostasis | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for intracellular calcium ion homeostasis (P-type Ca2+ ATPase node). Reason: By pumping Ca2+ out of the cytosol into the ER/SR, SERCA2 is a principal determinant of resting cytosolic and ER Ca2+ levels; it does part of the work of intracellular Ca2+ homeostasis. The node is seeded by SERCA, SPCA and related Ca2+-pump members across eukaryotes; rat Atp2a2 is squarely inside the clade with no sign of divergence. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. PMID:10748035 The sarco/endoplasmic reticulum calcium-ATPase (SERCA) translocates Ca(2+) from the cytosol to the lumen of the endoplasmic reticulum. |
| GO:0006874 intracellular calcium ion homeostasis | ISO GO_REF:0000121 | ACCEPT | Summary: ISO (mouse) intracellular calcium ion homeostasis. Reason: By pumping Ca2+ out of the cytosol into the ER/SR, SERCA2 is a principal determinant of resting cytosolic and ER Ca2+ levels; it does part of the work of intracellular Ca2+ homeostasis. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. |
| GO:0006874 intracellular calcium ion homeostasis | ISO GO_REF:0000121 | ACCEPT | Summary: ISO (human) intracellular calcium ion homeostasis. Reason: By pumping Ca2+ out of the cytosol into the ER/SR, SERCA2 is a principal determinant of resting cytosolic and ER Ca2+ levels; it does part of the work of intracellular Ca2+ homeostasis. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. |
| GO:0006874 intracellular calcium ion homeostasis | ISO GO_REF:0000121 | ACCEPT | Summary: ISO (human SERCA2a) intracellular calcium ion homeostasis. Reason: By pumping Ca2+ out of the cytosol into the ER/SR, SERCA2 is a principal determinant of resting cytosolic and ER Ca2+ levels; it does part of the work of intracellular Ca2+ homeostasis. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. |
| GO:0006937 regulation of muscle contraction | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA (ARBA) regulation of muscle contraction. Reason: SERCA2 activity in muscle sets the rate of Ca2+ removal and SR load and so shapes contraction and relaxation (PMID:9851937, PMID:21993782). True physiological role, non-core. Supporting Evidence: PMID:9851937 The present study demonstrates that increases in SERCA2a pump levels can directly enhance contractile function of the heart by increasing SR Ca2+ transport. PMID:21993782 Thapsigargin treatment revealed that SERCA activity determines fatigue resistance but does not affect maximal muscle force or contraction rates. |
| GO:0006984 ER-nucleus signaling pathway | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: ISO from mouse IMP (PMID:14561754, ER-stress cell death pathway). Reason: Loss or inhibition of SERCA2 depletes the ER Ca2+ store and thereby triggers ER stress signalling; SERCA2 is the perturbed upstream component, not a participant in the ER-to-nucleus signal transduction. Over-annotation of an indirect effect. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:88110 · Atp2a2 mouse SOURCE WEAK OR INFERRED Donor is a perturbation phenotype in which ER Ca2+ depletion induces ER stress (PMID:14561754). Supporting Evidence: PMID:10748035 The sarco/endoplasmic reticulum calcium-ATPase (SERCA) translocates Ca(2+) from the cytosol to the lumen of the endoplasmic reticulum. PMID:11595740 Depletion of SR calcium in cultured cardiac myocytes fostered the translocation of ATF6 from the ER to the nucleus, activated the promoter for rat SERCA2, and led to increased levels of SERCA2 protein. |
| GO:0008016 regulation of heart contraction | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA (ARBA) regulation of heart contraction. Reason: SERCA2a Ca2+ re-uptake controls cardiac relaxation and contractility (PMID:9851937, PMID:17901878). True, non-core physiological role. Supporting Evidence: PMID:9851937 The present study demonstrates that increases in SERCA2a pump levels can directly enhance contractile function of the heart by increasing SR Ca2+ transport. PMID:17901878 This prevents the subsequent release of PLN from SERCA2, thereby affecting the Ca(2+) re-uptake into the sarcoplasmic reticulum induced by adrenergic stimuli. |
| GO:0010666 positive regulation of cardiac muscle cell apoptotic process | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: ISO from mouse IDA (PMID:31819041, lncRNA ZFAS1 and cardiomyocyte apoptosis). Reason: The donor study shows that ZFAS1-mediated SERCA2a inhibition causes Ca2+ overload and apoptosis; SERCA2a loss of function promotes apoptosis, so SERCA2a does not positively regulate apoptosis. Indirect consequence of Ca2+ mishandling. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:88110 · Atp2a2 mouse SOURCE WEAK OR INFERRED Donor reports apoptosis secondary to SERCA2a inhibition and Ca2+ overload (PMID:31819041). Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. PMID:31819041 ZFAS1, an endogenous SERCA2a inhibitor, induces mitochondria-mediated apoptosis via cytosolic Ca2+ overload. |
| GO:0010882 regulation of cardiac muscle contraction by calcium ion signaling | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for regulation of cardiac muscle contraction by calcium ion signaling. Reason: SERCA2a re-sequesters Ca2+ released by RyR2, terminating the Ca2+ transient that couples excitation to contraction and setting SR load for the next beat; it directly performs a step of cardiac Ca2+ signalling for contraction. The node is seeded by rat Atp2a2 itself and human ATP2A2, which is expected. Supporting Evidence: PMID:9851937 The present study demonstrates that increases in SERCA2a pump levels can directly enhance contractile function of the heart by increasing SR Ca2+ transport. PMID:17901878 This prevents the subsequent release of PLN from SERCA2, thereby affecting the Ca(2+) re-uptake into the sarcoplasmic reticulum induced by adrenergic stimuli. |
| GO:0010882 regulation of cardiac muscle contraction by calcium ion signaling | IDA PMID:9851937 Targeted overexpression of the sarcoplasmic reticulum Ca2+-A... | ACCEPT | Summary: IDA, SERCA2a overexpression increases Ca2+ transient amplitude and contractility (abstract). Reason: SERCA2a re-sequesters Ca2+ released by RyR2, terminating the Ca2+ transient that couples excitation to contraction and setting SR load for the next beat; it directly performs a step of cardiac Ca2+ signalling for contraction. Supporting Evidence: PMID:9851937 The present study demonstrates that increases in SERCA2a pump levels can directly enhance contractile function of the heart by increasing SR Ca2+ transport. |
| GO:0010882 regulation of cardiac muscle contraction by calcium ion signaling | ISO GO_REF:0000121 | ACCEPT | Summary: ISO (human SERCA2a). Reason: SERCA2a re-sequesters Ca2+ released by RyR2, terminating the Ca2+ transient that couples excitation to contraction and setting SR load for the next beat; it directly performs a step of cardiac Ca2+ signalling for contraction. Supporting Evidence: PMID:9851937 The present study demonstrates that increases in SERCA2a pump levels can directly enhance contractile function of the heart by increasing SR Ca2+ transport. |
| GO:0014704 intercalated disc | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: ISO intercalated disc from human SERCA2. Reason: SERCA2a is an SR membrane pump concentrated in the longitudinal SR of cardiomyocytes. Proximity of SR to the intercalated disc in immunostaining does not make SERCA2 a component of the disc junctional complex; the donor evidence could not be inspected here, and the claim is not supported for rat. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: UniProtKB:P16615 · ATP2A2 human UNRESOLVED Human source annotation not inspected; likely immunostaining of SR adjacent to the disc. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Sarcoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein |
| GO:0014801 longitudinal sarcoplasmic reticulum | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO longitudinal sarcoplasmic reticulum from human. Reason: SERCA pumps are concentrated in the longitudinal (free) SR, while RyR2 is in junctional SR; a correct, more specific muscle location, kept as non-core beside SR membrane. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Sarcoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein PMID:20177054 These findings suggest that SERCA2b serves an SR compartment proximal to the plasma membrane of pulmonary arterial smooth muscle cells, whereas SERCA2a serves a discrete SR compartment located centrally within these cells. |
| GO:0014883 transition between fast and slow fiber | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: ISO from mouse IDA (PMID:18978355, TEAD-1 overexpression slows skeletal muscle). Reason: In the donor study SERCA2 expression changes as a marker of a fast-to-slow fibre shift driven by TEAD-1; SERCA2 is an output of the fibre-type programme, not a participant in the transition. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:88110 · Atp2a2 mouse SOURCE WEAK OR INFERRED Donor records SERCA2 expression as a slow-fibre marker (PMID:18978355). Supporting Evidence: PMID:21993782 More rapid muscle relaxation was correlated with increased expression of troponin I type 2 (fast) isoform and decreased expression of SERCA2 (slow) isoform. |
| GO:0014898 cardiac muscle hypertrophy in response to stress | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: ISO from mouse IDA (PMID:24137001, pri-miR-208b/Ezh2 in heart). Reason: SERCA2a expression is a readout of the hypertrophic gene programme in the donor study; SERCA2 does not perform a step of hypertrophy. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:88110 · Atp2a2 mouse SOURCE WEAK OR INFERRED Donor uses SERCA2a expression as a hypertrophy marker (PMID:24137001). Supporting Evidence: PMID:25712896 lipopolysaccharide treatment significantly elevated the serum TNF-α level, as well as phosphorylation of IKK, resulting in a decrease in myocardial SERCA2a expression, diastolic calcium reuptake, and diastolic dysfunction. |
| GO:0016020 membrane | IBA GO_REF:0000033 | MODIFY | Summary: IBA membrane (P-type ATPase superfamily node). Reason: True but general. SERCA2 is a multi-pass membrane protein of the ER and SR; GO:0005789 ER membrane and GO:0033017 SR membrane, both carried by this gene, are the supported locations. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN001943383 SUPPORTS TRANSFER Deep P-type ATPase node correctly places a membrane location; it stops at membrane because members sit in different organelles. Proposed replacements: endoplasmic reticulum membrane sarcoplasmic reticulum membrane Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein file:rat/Atp2a2/Atp2a2-uniprot.txt Sarcoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: IEA (InterPro) membrane. Reason: True but general. SERCA2 is a multi-pass membrane protein of the ER and SR; GO:0005789 ER membrane and GO:0033017 SR membrane, both carried by this gene, are the supported locations. Proposed replacements: endoplasmic reticulum membrane sarcoplasmic reticulum membrane Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein file:rat/Atp2a2/Atp2a2-uniprot.txt Sarcoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein |
| GO:0016020 membrane | ISO GO_REF:0000121 | MODIFY | Summary: ISO membrane from mouse. Reason: True but general. SERCA2 is a multi-pass membrane protein of the ER and SR; GO:0005789 ER membrane and GO:0033017 SR membrane, both carried by this gene, are the supported locations. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:88110 · Atp2a2 mouse SUPPORTS TRANSFER Mouse membrane annotation is correct but less specific than ER/SR membrane. Proposed replacements: endoplasmic reticulum membrane sarcoplasmic reticulum membrane Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein file:rat/Atp2a2/Atp2a2-uniprot.txt Sarcoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein |
| GO:0016020 membrane | ISO GO_REF:0000121 | MODIFY | Summary: ISO membrane from human. Reason: True but general. SERCA2 is a multi-pass membrane protein of the ER and SR; GO:0005789 ER membrane and GO:0033017 SR membrane, both carried by this gene, are the supported locations. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P16615 · ATP2A2 human SUPPORTS TRANSFER Human membrane annotation is correct but less specific than ER/SR membrane. Proposed replacements: endoplasmic reticulum membrane sarcoplasmic reticulum membrane Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein file:rat/Atp2a2/Atp2a2-uniprot.txt Sarcoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein |
| GO:0016240 autophagosome membrane docking | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: ISO autophagosome membrane docking from human SERCA2. Reason: GO:0016240 is the initial attachment of an autophagosome to its target membrane during autophagosome maturation. The donor paper (human UniProt IDA, PMID:28890335) concerns VMP1-promoted SERCA activity controlling ER-isolation membrane contacts during autophagosome formation, i.e. biogenesis, not autophagosome docking. SERCA2 role in autophagy is captured by GO:0000045 autophagosome assembly (kept as non-core); the docking term misplaces it. Propagation Review Root cause: SOURCE BAD Failure modes: SOURCE MISCITATION Sources checked: UniProtKB:P16615 · ATP2A2 human SOURCE BAD Human IDA cites PMID:28890335, which shows ER-isolation membrane contact control in autophagosome formation, not docking. Supporting Evidence: PMID:28890335 VMP1 controls contact formation by promoting SERCA PMID:28890335 During autophagosome formation in mammalian cells, isolation membranes (IMs; autophagosome precursors) dynamically contact the ER. |
| GO:0016240 autophagosome membrane docking | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS autophagosome membrane docking from human SERCA2. Reason: GO:0016240 is the initial attachment of an autophagosome to its target membrane during autophagosome maturation. The donor paper (human UniProt IDA, PMID:28890335) concerns VMP1-promoted SERCA activity controlling ER-isolation membrane contacts during autophagosome formation, i.e. biogenesis, not autophagosome docking. SERCA2 role in autophagy is captured by GO:0000045 autophagosome assembly (kept as non-core); the docking term misplaces it. Propagation Review Root cause: SOURCE BAD Failure modes: SOURCE MISCITATION Sources checked: UniProtKB:P16615 · ATP2A2 human SOURCE BAD Human IDA cites PMID:28890335, which shows ER-isolation membrane contact control in autophagosome formation, not docking. Supporting Evidence: PMID:28890335 VMP1 controls contact formation by promoting SERCA PMID:28890335 During autophagosome formation in mammalian cells, isolation membranes (IMs; autophagosome precursors) dynamically contact the ER. |
| GO:0016529 sarcoplasmic reticulum | IDA PMID:12409282 Mechanisms underlying increases in SR Ca2+-ATPase activity a... | ACCEPT | Summary: IDA, SR vesicles from rat muscle (abstract only). Reason: Sarcoplasmic reticulum is the specialized muscle ER (GO:0016529 is_a GO:0005783) in which SERCA2a pumps Ca2+; informative organelle-level location, with SR membrane also carried. Vesicle assays cannot resolve the sub-compartment. Supporting Evidence: PMID:12409282 we analyzed Ca(2+)-ATPase activity and Ca(2+) uptake in SR vesicles from the fast rat gastrocnemius muscles |
| GO:0016529 sarcoplasmic reticulum | IDA PMID:17901878 AKAP complex regulates Ca2+ re-uptake into heart sarcoplasmi... | ACCEPT | Summary: IDA, SERCA2-PLN-AKAP18delta-PKA complex in rat heart SR (abstract only). Reason: Sarcoplasmic reticulum is the specialized muscle ER (GO:0016529 is_a GO:0005783) in which SERCA2a pumps Ca2+; informative organelle-level location, with SR membrane also carried. Supporting Evidence: PMID:17901878 we identified a supramolecular complex consisting of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2), its negative regulator phospholamban (PLN), the A-kinase anchoring protein AKAP18delta and PKA. |
| GO:0016529 sarcoplasmic reticulum | IDA PMID:8447366 Molecular cloning and quantification of sarcoplasmic reticul... | ACCEPT | Summary: IDA, quantification of SERCA isoform protein in rat muscle SR (abstract only). Reason: Sarcoplasmic reticulum is the specialized muscle ER (GO:0016529 is_a GO:0005783) in which SERCA2a pumps Ca2+; informative organelle-level location, with SR membrane also carried. Supporting Evidence: PMID:8447366 Quantitative immunoblotting was also used to determine the protein content of each SERCA isoform. |
| GO:0016529 sarcoplasmic reticulum | IEA GO_REF:0000117 | ACCEPT | Summary: IEA (ARBA) sarcoplasmic reticulum. Reason: Sarcoplasmic reticulum is the specialized muscle ER (GO:0016529 is_a GO:0005783) in which SERCA2a pumps Ca2+; informative organelle-level location, with SR membrane also carried. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Sarcoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein |
| GO:0016529 sarcoplasmic reticulum | ISO GO_REF:0000121 | ACCEPT | Summary: ISO SR from mouse. Reason: Sarcoplasmic reticulum is the specialized muscle ER (GO:0016529 is_a GO:0005783) in which SERCA2a pumps Ca2+; informative organelle-level location, with SR membrane also carried. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Sarcoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein |
| GO:0016529 sarcoplasmic reticulum | ISO GO_REF:0000121 | ACCEPT | Summary: ISO SR from human. Reason: Sarcoplasmic reticulum is the specialized muscle ER (GO:0016529 is_a GO:0005783) in which SERCA2a pumps Ca2+; informative organelle-level location, with SR membrane also carried. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Sarcoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein |
| GO:0016529 sarcoplasmic reticulum | ISO GO_REF:0000121 | ACCEPT | Summary: ISO SR from human SERCA2b. Reason: Sarcoplasmic reticulum is the specialized muscle ER (GO:0016529 is_a GO:0005783) in which SERCA2a pumps Ca2+; informative organelle-level location, with SR membrane also carried. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Sarcoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein |
| GO:0016529 sarcoplasmic reticulum | TAS PMID:11595740 Sarco/endoplasmic reticulum calcium ATPase-2 expression is r... | ACCEPT | Summary: TAS, ATF6/SERCA2 cardiac myocyte paper. Reason: Sarcoplasmic reticulum is the specialized muscle ER (GO:0016529 is_a GO:0005783) in which SERCA2a pumps Ca2+; informative organelle-level location, with SR membrane also carried. Supporting Evidence: PMID:11595740 sarco/endoplasmic reticulum calcium ATPase-2 (SERCA2), a protein that transports calcium into the SR from the cytoplasm. |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: IEA (InterPro P-type ATPase) ATP hydrolysis activity. Reason: SERCA2 does hydrolyse ATP (measured for rat SERCA2a, PMID:21300842), but the hydrolysis is obligatorily coupled to Ca2+ translocation and is captured within P-type calcium transporter activity. Kept as a true, non-core activity. Supporting Evidence: PMID:21300842 Total ventricular SERCA2a protein remained unchanged, but its ability to hydrolyze ATP and transport Ca(2+) was significantly reduced. |
| GO:0019899 enzyme binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO enzyme binding from mouse. Reason: SERCA2 binds several enzymes (e.g. PDE4D in the cardiac SR complex in the donor study PMID:21903937; ULK1; PKA in the AKAP18delta complex). Enzyme binding is true but uninformative and peripheral to the pump function; non-core. Supporting Evidence: PMID:17901878 we identified a supramolecular complex consisting of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2), its negative regulator phospholamban (PLN), the A-kinase anchoring protein AKAP18delta and PKA. PMID:21903937 PDE4D coimmunoprecipitated with SERCA2a but not with cardiac ryanodine receptor. |
| GO:0019899 enzyme binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO enzyme binding from human. Reason: SERCA2 binds several enzymes (e.g. PDE4D in the cardiac SR complex in the donor study PMID:21903937; ULK1; PKA in the AKAP18delta complex). Enzyme binding is true but uninformative and peripheral to the pump function; non-core. Supporting Evidence: PMID:17901878 we identified a supramolecular complex consisting of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2), its negative regulator phospholamban (PLN), the A-kinase anchoring protein AKAP18delta and PKA. PMID:21903937 PDE4D coimmunoprecipitated with SERCA2a but not with cardiac ryanodine receptor. |
| GO:0031234 extrinsic component of cytoplasmic side of plasma membrane | IDA PMID:20177054 Identification of functionally segregated sarcoplasmic retic... | MODIFY | Summary: IDA in rat pulmonary arterial smooth muscle cells: SERCA2b labelling within 1.5 um of the plasma membrane (full text read). Reason: The paper shows SERCA2b concentrated in a subplasmalemmal SR compartment, explicitly described as "an SR compartment proximal to the plasma membrane". SERCA2 is an integral multi-pass SR/ER membrane protein; nothing in the paper shows it as a peripheral protein on the cytoplasmic face of the plasma membrane. The location assayed is peripheral SR membrane; GO:0033017 SR membrane is the correct term. Proposed replacements: sarcoplasmic reticulum membrane Supporting Evidence: PMID:20177054 In marked contrast, SERCA2b labeling was primarily found within 1.5 microm of the plasma membrane, where labeling for RyR1 was maximal. PMID:20177054 These findings suggest that SERCA2b serves an SR compartment proximal to the plasma membrane of pulmonary arterial smooth muscle cells, whereas SERCA2a serves a discrete SR compartment located centrally within these cells. file:rat/Atp2a2/Atp2a2-uniprot.txt Sarcoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein |
| GO:0031775 lutropin-choriogonadotropic hormone receptor binding | IPI PMID:17588601 The endoplasmic reticulum Ca2+-pump SERCA2b interacts with G... | KEEP AS NON CORE | Summary: IPI with LH receptor in rat ovary (abstract only). Reason: SERCA2b transiently associates with newly synthesized family A GPCRs, including endogenous LH receptor in rat ovary, and its pump activity aids receptor maturation. A real but peripheral interaction; the receptor-binding MF is the term GO offers for it. Non-core. Supporting Evidence: PMID:17588601 was shown to occur also between the endogenously expressed luteinizing hormone receptor and SERCA2b in rat ovaries PMID:17588601 we propose that the association with SERCA2b is required for efficient folding and/or membrane integration of G protein-coupled receptors. |
| GO:0032469 endoplasmic reticulum calcium ion homeostasis | ISO GO_REF:0000121 | ACCEPT | Summary: ISO ER calcium ion homeostasis from human. Reason: SERCA2 is the main pump that loads and maintains the ER/SR Ca2+ store; it directly performs ER Ca2+ homeostasis. Supporting Evidence: PMID:10748035 The sarco/endoplasmic reticulum calcium-ATPase (SERCA) translocates Ca(2+) from the cytosol to the lumen of the endoplasmic reticulum. file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. PMID:16402920 All SERCA2 proteins induced an increased Ca2+ content in the ER of intact transfected cells. |
| GO:0032469 endoplasmic reticulum calcium ion homeostasis | ISO GO_REF:0000121 | ACCEPT | Summary: ISO ER calcium ion homeostasis from human SERCA2a. Reason: SERCA2 is the main pump that loads and maintains the ER/SR Ca2+ store; it directly performs ER Ca2+ homeostasis. Supporting Evidence: PMID:10748035 The sarco/endoplasmic reticulum calcium-ATPase (SERCA) translocates Ca(2+) from the cytosol to the lumen of the endoplasmic reticulum. file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. |
| GO:0032470 positive regulation of endoplasmic reticulum calcium ion concentration | ISO GO_REF:0000121 | ACCEPT | Summary: ISO (mouse IMP, PMID:30188326) positive regulation of ER Ca2+ concentration. Reason: SERCA2 is the main pump that loads and maintains the ER/SR Ca2+ store; it directly performs ER Ca2+ homeostasis. Pumping Ca2+ into the lumen raises ER Ca2+ concentration directly. Supporting Evidence: PMID:10748035 The sarco/endoplasmic reticulum calcium-ATPase (SERCA) translocates Ca(2+) from the cytosol to the lumen of the endoplasmic reticulum. |
| GO:0032470 positive regulation of endoplasmic reticulum calcium ion concentration | ISO GO_REF:0000121 | ACCEPT | Summary: ISO (human) positive regulation of ER Ca2+ concentration. Reason: SERCA2 is the main pump that loads and maintains the ER/SR Ca2+ store; it directly performs ER Ca2+ homeostasis. Pumping Ca2+ into the lumen raises ER Ca2+ concentration directly. Supporting Evidence: PMID:10748035 The sarco/endoplasmic reticulum calcium-ATPase (SERCA) translocates Ca(2+) from the cytosol to the lumen of the endoplasmic reticulum. |
| GO:0032496 response to lipopolysaccharide | IEP PMID:25712896 TNF-α down-regulates sarcoplasmic reticulum Ca²⁺ ATPase expr... | KEEP AS NON CORE | Summary: IEP: LPS treatment of rats lowers myocardial SERCA2a expression (abstract). Reason: Expression evidence: LPS (via TNF-alpha/NF-kB) represses SERCA2a in rat heart. Under GO IEP conventions this supports response to LPS as a transcriptional response of the gene; it says nothing about SERCA2 function. Non-core. Supporting Evidence: PMID:25712896 lipopolysaccharide treatment significantly elevated the serum TNF-α level, as well as phosphorylation of IKK, resulting in a decrease in myocardial SERCA2a expression, diastolic calcium reuptake, and diastolic dysfunction. |
| GO:0032991 protein-containing complex | IDA PMID:17901878 AKAP complex regulates Ca2+ re-uptake into heart sarcoplasmi... | KEEP AS NON CORE | Summary: IDA protein-containing complex: SERCA2-PLN-AKAP18delta-PKA (abstract only). Reason: The paper identifies a supramolecular SERCA2/PLN/AKAP18delta/PKA complex in rat heart that controls adrenergic Ca2+ re-uptake. No specific GO complex term describes this AKAP signalling assembly, so the general term is as precise as the evidence allows; non-core. Supporting Evidence: PMID:17901878 we identified a supramolecular complex consisting of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2), its negative regulator phospholamban (PLN), the A-kinase anchoring protein AKAP18delta and PKA. PMID:17901878 This prevents the subsequent release of PLN from SERCA2, thereby affecting the Ca(2+) re-uptake into the sarcoplasmic reticulum induced by adrenergic stimuli. |
| GO:0033017 sarcoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA from UniProt subcellular location. Reason: SERCA2 is an integral multi-pass SR membrane protein in muscle cells, where it pumps Ca2+ into the SR lumen; core location. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Sarcoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein |
| GO:0033017 sarcoplasmic reticulum membrane | ISO GO_REF:0000121 | ACCEPT | Summary: ISO SR membrane from mouse. Reason: SERCA2 is an integral multi-pass SR membrane protein in muscle cells, where it pumps Ca2+ into the SR lumen; core location. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Sarcoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein |
| GO:0033017 sarcoplasmic reticulum membrane | ISO GO_REF:0000121 | ACCEPT | Summary: ISO SR membrane from pig ATP2A2. Reason: SERCA2 is an integral multi-pass SR membrane protein in muscle cells, where it pumps Ca2+ into the SR lumen; core location. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Sarcoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein |
| GO:0033017 sarcoplasmic reticulum membrane | ISO GO_REF:0000121 | ACCEPT | Summary: ISO SR membrane from human. Reason: SERCA2 is an integral multi-pass SR membrane protein in muscle cells, where it pumps Ca2+ into the SR lumen; core location. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Sarcoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein |
| GO:0033017 sarcoplasmic reticulum membrane | ISO GO_REF:0000121 | ACCEPT | Summary: ISO SR membrane from human (all isoforms). Reason: SERCA2 is an integral multi-pass SR membrane protein in muscle cells, where it pumps Ca2+ into the SR lumen; core location. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Sarcoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein |
| GO:0033017 sarcoplasmic reticulum membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ISS SR membrane from mouse. Reason: SERCA2 is an integral multi-pass SR membrane protein in muscle cells, where it pumps Ca2+ into the SR lumen; core location. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Sarcoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein |
| GO:0033292 T-tubule organization | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: ISO from mouse IMP (PMID:22355118, Serca2 knockout cardiomyocytes). Reason: In the donor study, cardiomyocyte Serca2 knockout causes SR volume loss with compensatory T-tubule remodelling. The T-tubule change is a secondary adaptation; SERCA2 does not do any of the work of organising T-tubules. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:88110 · Atp2a2 mouse SOURCE WEAK OR INFERRED Donor reports compensatory T-tubule remodelling after Serca2 KO (PMID:22355118). Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. PMID:22355118 major reduction in sarcoplasmic reticulum (SR) function in mice with Serca2 knockout (KO) is compensated by enhanced plasmalemmal Ca(2+) fluxes. |
| GO:0034599 cellular response to oxidative stress | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: ISO from mouse IGI (PMID:25452428, SEPN1 redox regulation of SERCA2). Reason: In the donor study SEPN1 protects SERCA2 from hyperoxidation; SERCA2 is the redox target, and its inclusion in a response-to-oxidative-stress process reflects being acted upon, not performing a step of the response. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:88110 · Atp2a2 mouse SOURCE WEAK OR INFERRED Donor shows SERCA2 as the oxidised target of SEPN1 (PMID:25452428). Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. PMID:25452428 SEPN1 enhances SERCA2 activity by reducing luminal cysteines that are hyperoxidized by ERO1-generated peroxides. |
| GO:0034605 cellular response to heat | IEP PMID:10748035 The sarco/endoplasmic reticulum calcium-ATPase 2b is an endo... | UNDECIDED | Summary: IEP: SERCA2b induction in PC12 cells (abstract only). Reason: The abstract describes SERCA2b induction by ER stress agents (tunicamycin, DTT, azetidine carboxylic acid), with no mention of heat. Heat shock may appear in the full text, which is not available here, so the row cannot be checked. Any such response would be expression-level, not a function of SERCA2. Supporting Evidence: PMID:10748035 Induction of ER stress by tunicamycin, dithiothreitol, or l-azetidine 2-carboxylic acid did not result in depletion of ER calcium |
| GO:0044325 transmembrane transporter binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO from human IPI with TRPC1 (PMID:18068335). Reason: The donor study reports SERCA2b association with TRPC1 in platelets. Transmembrane transporter binding is a true but peripheral interaction; non-core. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. |
| GO:0044548 S100 protein binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO S100 protein binding from human (IPI with S100A1, PMID:12804600). Reason: S100A1 binds SERCA2a in a Ca2+-dependent manner and modulates its activity. Real interaction, non-core. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Interacts with S100A1 in a Ca(2+)-dependent manner PMID:12804600 We detected the formation of a Ca(2+)-dependent complex of S100A1 with SERCA2a and PLB in the human myocardium. |
| GO:0045822 negative regulation of heart contraction | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: ISO from mouse IGI (PMID:10555147 with Pln). Reason: The donor study shows that ablating phospholamban, the SERCA2a inhibitor, rescues dilated cardiomyopathy; the negative regulator of contraction in that system is PLN. SERCA2a raises contractility when overexpressed (PMID:9851937), so negative regulation of heart contraction inverts its role. The positive physiological role is captured by GO:0002026 and GO:0010882 rows. Propagation Review Root cause: SOURCE BAD Failure modes: REGULATORY SIGN INVERSION Sources checked: MGI:MGI:88110 · Atp2a2 mouse SOURCE BAD Mouse IGI (PMID:10555147) assigns the PLN inhibitory effect to SERCA2. Supporting Evidence: PMID:10555147 The ablation of a muscle-specific sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) inhibitor, phospholamban, rescued the spectrum of phenotypes that resemble human heart failure. PMID:9851937 The present study demonstrates that increases in SERCA2a pump levels can directly enhance contractile function of the heart by increasing SR Ca2+ transport. |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:20177054 Identification of functionally segregated sarcoplasmic retic... | KEEP AS NON CORE | Summary: IDA: SERCA2a labelling restricted to the perinuclear region of rat pulmonary arterial smooth muscle cells (full text read). Reason: Directly observed for SERCA2a in PASMCs, in perinuclear SR. A real, cell-type-specific distribution; non-core. Supporting Evidence: PMID:20177054 Almost all SERCA2a and RyR3 labeling was restricted to a region within 1.5 microm of the nucleus. PMID:20177054 These findings suggest that SERCA2b serves an SR compartment proximal to the plasma membrane of pulmonary arterial smooth muscle cells, whereas SERCA2a serves a discrete SR compartment located centrally within these cells. |
| GO:0055119 relaxation of cardiac muscle | IDA PMID:9851937 Targeted overexpression of the sarcoplasmic reticulum Ca2+-A... | ACCEPT | Summary: IDA, faster relaxation in SERCA2a-overexpressing hearts (abstract). Reason: Cardiac relaxation requires removal of cytosolic Ca2+ largely by SERCA2a pumping it into the SR; SERCA2a overexpression shortens relaxation and its loss slows it (PMID:9851937, PMID:21300842). SERCA2a performs this step. Supporting Evidence: PMID:9851937 time to peak pressure and time to half relaxation PMID:9851937 The maximum velocity of Ca2+ uptake (Vmax) was increased by 37%, demonstrating that increased pump levels result in increased SR Ca2+ uptake function. |
| GO:0055119 relaxation of cardiac muscle | ISO GO_REF:0000121 | ACCEPT | Summary: ISO (human SERCA2a) relaxation of cardiac muscle. Reason: Cardiac relaxation requires removal of cytosolic Ca2+ largely by SERCA2a pumping it into the SR; SERCA2a overexpression shortens relaxation and its loss slows it (PMID:9851937, PMID:21300842). SERCA2a performs this step. Supporting Evidence: PMID:9851937 The maximum velocity of Ca2+ uptake (Vmax) was increased by 37%, demonstrating that increased pump levels result in increased SR Ca2+ uptake function. PMID:21300842 Total ventricular SERCA2a protein remained unchanged, but its ability to hydrolyze ATP and transport Ca(2+) was significantly reduced. |
| GO:0061831 apical ectoplasmic specialization | IDA PMID:28486663 Ca2+ signaling machinery is present at intercellular junctio... | KEEP AS NON CORE | Summary: IDA: SERCA2 at apical ectoplasmic specializations of rat Sertoli cells (abstract only). Reason: Immunolocalisation places SERCA2 in the ER cisternae that form part of Sertoli cell ectoplasmic specializations. Real, tissue-specific location; non-core. Supporting Evidence: PMID:28486663 Sarco/endoplasmic reticulum Ca2+-ATPase 2 (ATP2A2, SERCA2) is present at ESs |
| GO:0070296 sarcoplasmic reticulum calcium ion transport | IDA PMID:21300842 Carbonylation contributes to SERCA2a activity loss and diast... | MODIFY | Summary: IDA, rat heart SERCA2a Ca2+ uptake (full text read). Reason: True but general. SERCA2 transports Ca2+ into (not out of or within) the SR; GO:1990036 calcium ion import into sarcoplasmic reticulum (is_a GO:0070296, carried by this gene) is the precise term. Proposed replacements: calcium ion import into sarcoplasmic reticulum Supporting Evidence: PMID:21300842 Total ventricular SERCA2a protein remained unchanged, but its ability to hydrolyze ATP and transport Ca(2+) was significantly reduced. PMID:21300842 the ATP-driven pump that translocates Ca(2+) from the cytoplasm to the lumen of the sarcoplasmic reticulum |
| GO:0070296 sarcoplasmic reticulum calcium ion transport | ISO GO_REF:0000121 | MODIFY | Summary: ISO from mouse IMP (PMID:22355118). Reason: True but general. SERCA2 transports Ca2+ into (not out of or within) the SR; GO:1990036 calcium ion import into sarcoplasmic reticulum (is_a GO:0070296, carried by this gene) is the precise term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:88110 · Atp2a2 mouse SUPPORTS TRANSFER Serca2 KO loss of SR Ca2+ transport is correct but less specific than import into SR. Proposed replacements: calcium ion import into sarcoplasmic reticulum Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. |
| GO:0070588 calcium ion transmembrane transport | IBA GO_REF:0000033 | MODIFY | Summary: IBA calcium ion transmembrane transport (P-type Ca2+ ATPase node). Reason: True but general. SERCA2 moves Ca2+ across the ER/SR membrane from cytosol to lumen; GO:1903515 (is_a GO:0070588) and GO:1990036, both carried by this gene, give the direction and compartment. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN002450634 SUPPORTS TRANSFER Node spans SERCA, SPCA and PMCA-like pumps of different membranes, so it stops at transmembrane transport. Proposed replacements: calcium ion transport from cytosol to endoplasmic reticulum calcium ion import into sarcoplasmic reticulum Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. PMID:21300842 Total ventricular SERCA2a protein remained unchanged, but its ability to hydrolyze ATP and transport Ca(2+) was significantly reduced. |
| GO:0070588 calcium ion transmembrane transport | IDA PMID:9851937 Targeted overexpression of the sarcoplasmic reticulum Ca2+-A... | MODIFY | Summary: IDA, SERCA2a overexpression raises SR Ca2+ uptake (abstract). Reason: True but general. SERCA2 moves Ca2+ across the ER/SR membrane from cytosol to lumen; GO:1903515 (is_a GO:0070588) and GO:1990036, both carried by this gene, give the direction and compartment. Proposed replacements: calcium ion transport from cytosol to endoplasmic reticulum calcium ion import into sarcoplasmic reticulum Supporting Evidence: PMID:9851937 The maximum velocity of Ca2+ uptake (Vmax) was increased by 37%, demonstrating that increased pump levels result in increased SR Ca2+ uptake function. |
| GO:0070588 calcium ion transmembrane transport | ISO GO_REF:0000121 | MODIFY | Summary: ISO from mouse. Reason: True but general. SERCA2 moves Ca2+ across the ER/SR membrane from cytosol to lumen; GO:1903515 (is_a GO:0070588) and GO:1990036, both carried by this gene, give the direction and compartment. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:88110 · Atp2a2 mouse SUPPORTS TRANSFER Correct, less specific than cytosol-to-ER transport. Proposed replacements: calcium ion transport from cytosol to endoplasmic reticulum calcium ion import into sarcoplasmic reticulum Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. |
| GO:0070588 calcium ion transmembrane transport | ISO GO_REF:0000121 | MODIFY | Summary: ISO from human. Reason: True but general. SERCA2 moves Ca2+ across the ER/SR membrane from cytosol to lumen; GO:1903515 (is_a GO:0070588) and GO:1990036, both carried by this gene, give the direction and compartment. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P16615 · ATP2A2 human SUPPORTS TRANSFER Correct, less specific than cytosol-to-ER transport. Proposed replacements: calcium ion transport from cytosol to endoplasmic reticulum calcium ion import into sarcoplasmic reticulum Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. |
| GO:0086036 regulation of cardiac muscle cell membrane potential | IDA PMID:9851937 Targeted overexpression of the sarcoplasmic reticulum Ca2+-A... | UNDECIDED | Summary: IDA (BHF-UCL) from the SERCA2a overexpression paper (abstract only). Reason: SERCA2 is an intracellular pump of the SR/ER; it affects sarcolemmal membrane potential only indirectly, through cytosolic Ca2+ and Ca2+-dependent currents such as NCX. The abstract reports Ca2+ uptake, Ca2+ transients and contractility but no membrane potential measurement; the full text, which the curator read, is not available here, so the row cannot be verified. Supporting Evidence: PMID:9851937 The present study demonstrates that increases in SERCA2a pump levels can directly enhance contractile function of the heart by increasing SR Ca2+ transport. |
| GO:0086036 regulation of cardiac muscle cell membrane potential | ISO GO_REF:0000121 | UNDECIDED | Summary: ISO from human (BHF-UCL IDA PMID:16402920, SERCA2c). Reason: SERCA2 is an intracellular pump of the SR/ER; it affects sarcolemmal membrane potential only indirectly, through cytosolic Ca2+ and Ca2+-dependent currents such as NCX. The human source (SERCA2c isoform study) could not be inspected; undecided pending the source. The cached abstract of PMID:16402920 describes SERCA2c expression and Ca2+ loading in HEK-293 cells, with no cardiac membrane-potential assay. Propagation Review Root cause: UNRESOLVED Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P16615 · ATP2A2 human UNRESOLVED Human IDA PMID:16402920 not cached; cannot verify a membrane-potential assay. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. PMID:16402920 All SERCA2 proteins induced an increased Ca2+ content in the ER of intact transfected cells. |
| GO:0086039 P-type calcium transporter activity involved in regulation of cardiac muscle cell membrane potential | IBA GO_REF:0000033 | MODIFY | Summary: IBA for the precomposed cardiac membrane-potential P-type Ca2+ transporter term. Reason: Precomposed "X involved in Y" term. X, P-type calcium transporter activity, is the core activity of SERCA2. Y, regulation of cardiac muscle cell membrane potential, is at most an indirect consequence of SR Ca2+ uptake and is not established for SERCA2; it is dropped. MODIFY to the genus GO:0005388. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH CONTEXT OR TISSUE MISMATCH Sources checked: PANTHER:PTN000643405 SUPPORTS TRANSFER SERCA node correctly carries Ca2+-pump activity; the cardiac membrane-potential context is not a heritable molecular property. Proposed replacements: P-type calcium transporter activity Context of precomposed term: context dropped Decomposed from precomposed GO:0086039 (projects/INVOLVED_IN_PRECOMPOSITION.md); the membrane-potential context is indirect for an SR/ER pump. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. PMID:21300842 Total ventricular SERCA2a protein remained unchanged, but its ability to hydrolyze ATP and transport Ca(2+) was significantly reduced. |
| GO:0086039 P-type calcium transporter activity involved in regulation of cardiac muscle cell membrane potential | ISO GO_REF:0000121 | MODIFY | Summary: ISO for the precomposed term from human. Reason: Precomposed "X involved in Y" term. X, P-type calcium transporter activity, is the core activity of SERCA2. Y, regulation of cardiac muscle cell membrane potential, is at most an indirect consequence of SR Ca2+ uptake and is not established for SERCA2; it is dropped. MODIFY to the genus GO:0005388. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P16615 · ATP2A2 human SUPPORTS TRANSFER Human pump activity transfers; membrane-potential context does not add a supported claim. Proposed replacements: P-type calcium transporter activity Context of precomposed term: context dropped Decomposed from precomposed GO:0086039 (projects/INVOLVED_IN_PRECOMPOSITION.md); the membrane-potential context is indirect for an SR/ER pump. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. PMID:21300842 Total ventricular SERCA2a protein remained unchanged, but its ability to hydrolyze ATP and transport Ca(2+) was significantly reduced. |
| GO:0086039 P-type calcium transporter activity involved in regulation of cardiac muscle cell membrane potential | ISS GO_REF:0000024 | MODIFY | Summary: ISS for the precomposed term from human. Reason: Precomposed "X involved in Y" term. X, P-type calcium transporter activity, is the core activity of SERCA2. Y, regulation of cardiac muscle cell membrane potential, is at most an indirect consequence of SR Ca2+ uptake and is not established for SERCA2; it is dropped. MODIFY to the genus GO:0005388. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P16615 · ATP2A2 human SUPPORTS TRANSFER Human pump activity transfers; the cardiac membrane-potential context is not an established SERCA2 role. Proposed replacements: P-type calcium transporter activity Context of precomposed term: context dropped Decomposed from precomposed GO:0086039 (projects/INVOLVED_IN_PRECOMPOSITION.md); the membrane-potential context is indirect for an SR/ER pump. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. PMID:21300842 Total ventricular SERCA2a protein remained unchanged, but its ability to hydrolyze ATP and transport Ca(2+) was significantly reduced. |
| GO:0090076 relaxation of skeletal muscle | IEP PMID:21993782 Variation in expression of calcium-handling proteins is asso... | KEEP AS NON CORE | Summary: IEP: SERCA2 expression inversely correlates with relaxation rate in rat gastrocnemius (abstract only). Reason: SERCA pumps remove cytosolic Ca2+ to relax skeletal muscle, and SERCA2 is the slow-fibre isoform; the process claim is biologically true. The cited evidence is correlative expression plus pan-SERCA thapsigargin, so it is weak, but the role in relaxation of slow fibres is well established. Non-core relative to cardiac function. Supporting Evidence: PMID:21993782 More rapid muscle relaxation was correlated with increased expression of troponin I type 2 (fast) isoform and decreased expression of SERCA2 (slow) isoform. PMID:21993782 Thapsigargin treatment revealed that SERCA activity determines fatigue resistance but does not affect maximal muscle force or contraction rates. |
| GO:0090534 calcium ion-transporting ATPase complex | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO calcium ion-transporting ATPase complex from human. Reason: SERCA2 is catalytically active as a single polypeptide, but it forms regulatory complexes with PLN, SLN and other micropeptides. The complex term is true in that sense and peripheral to the core pump function. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Reversibly inhibited by phospholamban (PLN) at low calcium concentrations. PMID:17901878 we identified a supramolecular complex consisting of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2), its negative regulator phospholamban (PLN), the A-kinase anchoring protein AKAP18delta and PKA. |
| GO:0097470 ribbon synapse | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO ribbon synapse from mouse IDA (PMID:19932743, rod photoreceptor CICR). Reason: In mouse rods, ER Ca2+ stores with SERCA2 lie at the ribbon synapse and support CICR-driven release. A real, cell-type-specific location of the ER pump; non-core. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:O55143}; Multi-pass membrane protein PMID:19932743 showed a close association between ER and synaptic ribbons in mouse rod terminals. |
| GO:0098909 regulation of cardiac muscle cell action potential involved in regulation of contraction | IDA PMID:9851937 Targeted overexpression of the sarcoplasmic reticulum Ca2+-A... | UNDECIDED | Summary: IDA (BHF-UCL) from the SERCA2a overexpression paper (abstract only). Reason: SERCA2 is an intracellular pump of the SR/ER; it affects sarcolemmal membrane potential only indirectly, through cytosolic Ca2+ and Ca2+-dependent currents such as NCX. The abstract does not report action potential recordings; the full text is not available here, so the row cannot be verified. Supporting Evidence: PMID:9851937 The present study demonstrates that increases in SERCA2a pump levels can directly enhance contractile function of the heart by increasing SR Ca2+ transport. |
| GO:0106222 lncRNA binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO lncRNA binding from mouse IPI (PMID:29475982, lncRNA ZFAS1). Reason: In mouse myocardial infarction, lncRNA ZFAS1 binds SERCA2a and inhibits it. The binding is a regulatory input to SERCA2a, real but peripheral; non-core. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. PMID:29475982 ZFAS1 was found to directly bind SERCA2a protein and to limit its activity, as well as to repress its expression. |
| GO:0120025 plasma membrane bounded cell projection | IDA PMID:28486663 Ca2+ signaling machinery is present at intercellular junctio... | KEEP AS NON CORE | Summary: IDA: SERCA2 in apical Sertoli cell processes (abstract only). Reason: Immunolocalisation of SERCA2-containing ER in apical Sertoli cell processes; real, tissue-specific; non-core. Supporting Evidence: PMID:28486663 Sarco/endoplasmic reticulum Ca2+-ATPase 2 (ATP2A2, SERCA2) is present at ESs PMID:28486663 Using electron microscopy, we define two new ER-plasma membrane (PM) contact sites in apical Sertoli cell processes. |
| GO:1903233 regulation of calcium ion-dependent exocytosis of neurotransmitter | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: ISO from mouse IMP (PMID:21106823, 22q11 deletion model, presynaptic Ca2+). Reason: In the donor study SERCA2 upregulation in 22q11 deletion mice enhances presynaptic ER Ca2+ and release. SERCA2 shapes presynaptic Ca2+ by its pump activity; calling it a regulator of Ca2+-dependent exocytosis reads an indirect effect of store loading as a regulatory role. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:88110 · Atp2a2 mouse SOURCE WEAK OR INFERRED Donor reports altered release secondary to SERCA2 overexpression (PMID:21106823). Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. PMID:21106823 Enhanced neurotransmitter release in Df(16)1/+ mice coincided with altered calcium kinetics in CA3 presynaptic terminals and upregulated sarco(endo)plasmic reticulum calcium-ATPase type 2 (SERCA2). |
| GO:1903515 calcium ion transport from cytosol to endoplasmic reticulum | ISO GO_REF:0000121 | ACCEPT | Summary: ISO from human. Reason: SERCA2 pumps Ca2+ from the cytosol into the ER lumen; this is the direct process of its core activity. Supporting Evidence: PMID:10748035 The sarco/endoplasmic reticulum calcium-ATPase (SERCA) translocates Ca(2+) from the cytosol to the lumen of the endoplasmic reticulum. file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. PMID:16402920 All SERCA2 proteins induced an increased Ca2+ content in the ER of intact transfected cells. |
| GO:1903515 calcium ion transport from cytosol to endoplasmic reticulum | ISO GO_REF:0000121 | ACCEPT | Summary: ISO from human (all isoforms). Reason: SERCA2 pumps Ca2+ from the cytosol into the ER lumen; this is the direct process of its core activity. Supporting Evidence: PMID:10748035 The sarco/endoplasmic reticulum calcium-ATPase (SERCA) translocates Ca(2+) from the cytosol to the lumen of the endoplasmic reticulum. file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. |
| GO:1990036 calcium ion import into sarcoplasmic reticulum | IDA PMID:9851937 Targeted overexpression of the sarcoplasmic reticulum Ca2+-A... | ACCEPT | Summary: IDA, increased SR Ca2+ uptake with SERCA2a overexpression (abstract). Reason: SERCA2a pumps Ca2+ from the cytosol into the SR lumen of muscle cells; the direct process of its core activity. Supporting Evidence: PMID:9851937 The maximum velocity of Ca2+ uptake (Vmax) was increased by 37%, demonstrating that increased pump levels result in increased SR Ca2+ uptake function. |
| GO:1990036 calcium ion import into sarcoplasmic reticulum | IEA GO_REF:0000117 | ACCEPT | Summary: IEA (ARBA) calcium ion import into SR. Reason: SERCA2a pumps Ca2+ from the cytosol into the SR lumen of muscle cells; the direct process of its core activity. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. |
| GO:1990036 calcium ion import into sarcoplasmic reticulum | ISO GO_REF:0000121 | ACCEPT | Summary: ISO from mouse. Reason: SERCA2a pumps Ca2+ from the cytosol into the SR lumen of muscle cells; the direct process of its core activity. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. PMID:21300842 Total ventricular SERCA2a protein remained unchanged, but its ability to hydrolyze ATP and transport Ca(2+) was significantly reduced. |
| GO:1990036 calcium ion import into sarcoplasmic reticulum | ISO GO_REF:0000121 | ACCEPT | Summary: ISO from human. Reason: SERCA2a pumps Ca2+ from the cytosol into the SR lumen of muscle cells; the direct process of its core activity. Supporting Evidence: file:rat/Atp2a2/Atp2a2-uniprot.txt This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. PMID:21300842 Total ventricular SERCA2a protein remained unchanged, but its ability to hydrolyze ATP and transport Ca(2+) was significantly reduced. |
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Download this section (compressed HTML)Q: Should the RGD IDA of rat Atp2a2 to GO:0031234 extrinsic component of cytoplasmic side of plasma membrane (PMID:20177054) be repointed to GO:0033017 sarcoplasmic reticulum membrane, given that the paper places SERCA2b in subplasmalemmal SR?
Q: Does the BHF-UCL full-text reading of PMID:9851937 include membrane-potential or action-potential recordings that support GO:0086036 and GO:0098909, or do these rows rest on Ca2+ transient data?
Q: Should the human UniProt IDA to GO:0016240 autophagosome membrane docking (PMID:28890335) be replaced by GO:0000045 autophagosome assembly, and the rat ISO/ISS rows dropped?
Q: Should the MGI IGI of mouse Atp2a2 to GO:0045822 negative regulation of heart contraction (PMID:10555147) be reassigned, since phospholamban is the negative regulator in that study?
Experiment: Immuno-electron microscopy of rat PASMCs with isoform-specific SERCA2a/2b antibodies and an SR luminal marker, combined with surface biotinylation to test for any plasma-membrane-associated SERCA2b.
Hypothesis: Subplasmalemmal SERCA2b and perinuclear SERCA2a in pulmonary arterial smooth muscle reside in distinct SR membrane domains rather than on the plasma membrane.
Type: immuno-electron microscopy and surface biotinylation
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