CACNB3 encodes CaVbeta3, a cytosolic auxiliary (beta) subunit of high-voltage-activated voltage-gated calcium channels of the CaV1 (L-type) and CaV2 (notably N-type CaV2.2) classes. It is a membrane-associated-guanylate-kinase-like protein with an SH3 domain and a catalytically inactive guanylate-kinase-like domain; the GK domain binds the alpha-interaction domain in the cytoplasmic I-II linker of the pore-forming alpha1 subunit. Through this interaction beta3 promotes surface expression of the alpha1 subunit and increases peak current while shifting voltage-dependent activation and inactivation. It is the predominant beta subunit of many neurons, and is also expressed in smooth muscle, pancreatic beta-cells and other tissues. In mice, loss of beta3 reduces neuronal L- and N-type currents and dampens inflammatory pain processing. A channel-independent interaction with IP3 receptors that limits IP3-evoked calcium release has been reported in rodent cells.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005245 voltage-gated calcium channel activity | IDA PMID:11160515 Biophysical properties, pharmacology, and modulation of huma... | MODIFY | Summary: Bell et al. recorded high-voltage-activated L-type (CaV1.3) and N-type currents from reconstituted alpha1/alpha2delta-1/beta3 channels in HEK293 cells; beta3 is a subunit of the complex that carries the activity. Reason: The contributes_to qualifier makes a defensible, weaker claim, since beta3 is a non-pore subunit of the complex whose activity was measured. The activity beta3 itself performs is modulation of the alpha1 pore, which is calcium channel regulator activity; refining to that term keeps this row consistent with the enables rows for the same term, and complex membership is captured by the accepted channel-complex terms. Proposed replacements: calcium channel regulator activity Supporting Evidence: PMID:11160515 calcium channel currents formed by the human neuronal L-type alpha(1D) subunit, co-expressed with alpha(2)delta-1 and beta(3a) PMID:11160515 N-type currents, formed from transiently transfected alpha(1B)/alpha(2)delta-1/beta(3) |
| GO:0005245 voltage-gated calcium channel activity | IEA GO_REF:0000120 | MODIFY | Summary: CaVbeta3 is a cytosolic auxiliary subunit with no pore; the conducting activity belongs to the alpha1 subunit and beta3 modulates it. Reason: An enables claim of voltage-gated calcium channel activity overstates the role of a non-pore subunit. The experiments (Collin 1994 for human beta3; Castellano 1993 for beta3 coexpressed with cardiac alpha1) show modulation of channel currents, which is calcium channel regulator activity. The contributes_to row for this term is retained separately. Proposed replacements: calcium channel regulator activity Supporting Evidence: PMID:8119293 The cloned H beta 3 subunit was further expressed in Xenopus oocytes to demonstrate its ability to modulate VDCC activity. PMID:7679112 Coexpression of beta 3 with a cardiac alpha 1 in Xenopus oocytes induces similar changes in Ca2+ channel activity as beta 1 and beta 2, that is, it increases peak currents, modulates the voltage dependence of activation, and accelerates activation file:human/CACNB3/CACNB3-uniprot.txt Regulatory subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents (PubMed:8119293) |
| GO:0005245 voltage-gated calcium channel activity | TAS PMID:8119293 Cloning, chromosomal location and functional expression of t... | MODIFY | Summary: CaVbeta3 is a cytosolic auxiliary subunit with no pore; the conducting activity belongs to the alpha1 subunit and beta3 modulates it. Reason: An enables claim of voltage-gated calcium channel activity overstates the role of a non-pore subunit. The experiments (Collin 1994 for human beta3; Castellano 1993 for beta3 coexpressed with cardiac alpha1) show modulation of channel currents, which is calcium channel regulator activity. The contributes_to row for this term is retained separately. Proposed replacements: calcium channel regulator activity Supporting Evidence: PMID:8119293 The cloned H beta 3 subunit was further expressed in Xenopus oocytes to demonstrate its ability to modulate VDCC activity. PMID:7679112 Coexpression of beta 3 with a cardiac alpha 1 in Xenopus oocytes induces similar changes in Ca2+ channel activity as beta 1 and beta 2, that is, it increases peak currents, modulates the voltage dependence of activation, and accelerates activation file:human/CACNB3/CACNB3-uniprot.txt Regulatory subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents (PubMed:8119293) |
| GO:0005246 calcium channel regulator activity | ISS GO_REF:0000024 | ACCEPT | Summary: Core molecular function. Beta3 coexpression increases peak calcium current and shifts activation and inactivation of CaV1 and CaV2 alpha1 subunits. Reason: Directly shown for human beta3 (Collin 1994) and for rat beta3 with cardiac alpha1 (Castellano 1993); the ISS donor rat Cacnb3 (P54287) and human CACNB3 are in the same PANTHER subfamily (PTHR11824:SF8, beta-3), so the transfer is within the beta3 orthogroup. Mouse beta3 knockout reduces neuronal L- and N-type currents (Namkung 1998). Supporting Evidence: PMID:8119293 The cloned H beta 3 subunit was further expressed in Xenopus oocytes to demonstrate its ability to modulate VDCC activity. PMID:7679112 Coexpression of beta 3 with a cardiac alpha 1 in Xenopus oocytes induces similar changes in Ca2+ channel activity as beta 1 and beta 2, that is, it increases peak currents, modulates the voltage dependence of activation, and accelerates activation file:human/CACNB3/CACNB3-uniprot.txt Regulatory subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents (PubMed:8119293) PMID:9751781 in sympathetic beta3-/- neurons, the L- and N-type current was significantly reduced relative to wt file:human/CACNB3/CACNB3-deep-research-falcon.md non-enzymatic intracellular adapter, trafficking factor, and allosteric channel regulator |
| GO:0005246 calcium channel regulator activity | ISS PMID:25527503 Functional characterization of CaVΞ±2Ξ΄ mutations associated w... | ACCEPT | Summary: Core molecular function. Beta3 coexpression increases peak calcium current and shifts activation and inactivation of CaV1 and CaV2 alpha1 subunits. Reason: Directly shown for human beta3 (Collin 1994) and for rat beta3 with cardiac alpha1 (Castellano 1993); the ISS donor rat Cacnb3 (P54287) and human CACNB3 are in the same PANTHER subfamily (PTHR11824:SF8, beta-3), so the transfer is within the beta3 orthogroup. Mouse beta3 knockout reduces neuronal L- and N-type currents (Namkung 1998). Supporting Evidence: PMID:8119293 The cloned H beta 3 subunit was further expressed in Xenopus oocytes to demonstrate its ability to modulate VDCC activity. PMID:7679112 Coexpression of beta 3 with a cardiac alpha 1 in Xenopus oocytes induces similar changes in Ca2+ channel activity as beta 1 and beta 2, that is, it increases peak currents, modulates the voltage dependence of activation, and accelerates activation file:human/CACNB3/CACNB3-uniprot.txt Regulatory subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents (PubMed:8119293) PMID:9751781 in sympathetic beta3-/- neurons, the L- and N-type current was significantly reduced relative to wt |
| GO:0005515 protein binding | IPI PMID:18535142 Calmodulin-dependent gating of Ca(v)1.2 calcium channels in ... | MODIFY | Summary: Interaction with CACNA1C (CaV1.2 alpha1C), the pore-forming subunit of the L-type channel. CaVbeta subunits bind the alpha-interaction domain in the alpha1 I-II cytoplasmic linker. Reason: The partner is a transmembrane channel, so the informative molecular function is transmembrane transporter binding. Binding to alpha1 is the structural basis of the beta3 regulator activity and is also seen in the cryo-EM structures of beta3-containing human CaV1.2 and CaV2.2 complexes. Proposed replacements: transmembrane transporter binding Supporting Evidence: PMID:18535142 Ca(v)beta subunits are stably associated with the alpha(1C)-interaction domain site of the cytoplasmic linker between internal repeats I and II PMID:27481713 we expressed in Xenopus oocytes CaV1.2 channels consisting of Ξ±1C and Ξ²3 subunits |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen hit; the partner is not a known calcium-channel component and no functional consequence for CaVbeta3 has been shown. Reason: Bare protein binding carries no functional information. Removal follows the GO:0005515 policy and does not assert that the reported interaction is false; no more informative molecular function is supported by this screen for this partner. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Binary interaction with GEM, an RGK-family small GTPase. RGK GTPases are known to associate with CaVbeta subunits and inhibit channel function. Reason: Generic protein binding is uninformative; the partner is a small GTPase, so small GTPase binding is the more informative term literally supported by the screen. The functional consequence for beta3 (RGK-mediated channel inhibition) has not been shown in the cited high-throughput study, so this is kept as a binding statement only. Proposed replacements: small GTPase binding |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen hit; the partner is not a known calcium-channel component and no functional consequence for CaVbeta3 has been shown. Reason: Bare protein binding carries no functional information. Removal follows the GO:0005515 policy and does not assert that the reported interaction is false; no more informative molecular function is supported by this screen for this partner. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen hit; the partner is not a known calcium-channel component and no functional consequence for CaVbeta3 has been shown. Reason: Bare protein binding carries no functional information. Removal follows the GO:0005515 policy and does not assert that the reported interaction is false; no more informative molecular function is supported by this screen for this partner. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen hit; the partner is not a known calcium-channel component and no functional consequence for CaVbeta3 has been shown. Reason: Bare protein binding carries no functional information. Removal follows the GO:0005515 policy and does not assert that the reported interaction is false; no more informative molecular function is supported by this screen for this partner. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen hit; the partner is not a known calcium-channel component and no functional consequence for CaVbeta3 has been shown. Reason: Bare protein binding carries no functional information. Removal follows the GO:0005515 policy and does not assert that the reported interaction is false; no more informative molecular function is supported by this screen for this partner. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen hit; the partner is not a known calcium-channel component and no functional consequence for CaVbeta3 has been shown. Reason: Bare protein binding carries no functional information. Removal follows the GO:0005515 policy and does not assert that the reported interaction is false; no more informative molecular function is supported by this screen for this partner. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen hit; the partner is not a known calcium-channel component and no functional consequence for CaVbeta3 has been shown. Reason: Bare protein binding carries no functional information. Removal follows the GO:0005515 policy and does not assert that the reported interaction is false; no more informative molecular function is supported by this screen for this partner. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: High-throughput binary interaction screen hit; the partner is not a known calcium-channel component and no functional consequence for CaVbeta3 has been shown. Reason: Bare protein binding carries no functional information. Removal follows the GO:0005515 policy and does not assert that the reported interaction is false; no more informative molecular function is supported by this screen for this partner. |
| GO:0005515 protein binding | IPI PMID:37207277 Using brain cell-type-specific protein interactomes to inter... | MODIFY | Summary: Interaction with CACNA1C (CaV1.2 alpha1C), the pore-forming subunit of the L-type channel. CaVbeta subunits bind the alpha-interaction domain in the alpha1 I-II cytoplasmic linker. Reason: The partner is a transmembrane channel, so the informative molecular function is transmembrane transporter binding. Binding to alpha1 is the structural basis of the beta3 regulator activity and is also seen in the cryo-EM structures of beta3-containing human CaV1.2 and CaV2.2 complexes. Proposed replacements: transmembrane transporter binding Supporting Evidence: PMID:18535142 Ca(v)beta subunits are stably associated with the alpha(1C)-interaction domain site of the cytoplasmic linker between internal repeats I and II PMID:27481713 we expressed in Xenopus oocytes CaV1.2 channels consisting of Ξ±1C and Ξ²3 subunits |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: High-throughput binary interaction screen hit; the partner is not a known calcium-channel component and no functional consequence for CaVbeta3 has been shown. Reason: Bare protein binding carries no functional information. Removal follows the GO:0005515 policy and does not assert that the reported interaction is false; no more informative molecular function is supported by this screen for this partner. |
| GO:0005737 cytoplasm | EXP PMID:34234349 Structure of human Ca(v)2.2 channel blocked by the painkille... | ACCEPT | Summary: CaVbeta3 is a soluble cytoplasmic protein that docks on the intracellular face of the alpha1 subunit; the human CaV2.2 cryo-EM structure resolves beta3 on the cytoplasmic side of the channel. Reason: Supported by structure (Gao 2021, the EXP source), by the absence of any transmembrane segment, and by UniProt's curated subcellular location. Cytoplasm is as precise as the evidence for the free and channel-bound pools combined allows. Supporting Evidence: PMID:34234349 cryo-electron microscopy structures of human Cav2.2 (comprising the core Ξ±1 and the ancillary Ξ±2Ξ΄-1 and Ξ²3 subunits) file:human/CACNB3/CACNB3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:34234349} PMID:25527503 the cytoplasmic Ca V Ξ² auxiliary subunit |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: CaVbeta3 is a soluble cytoplasmic protein that docks on the intracellular face of the alpha1 subunit; the human CaV2.2 cryo-EM structure resolves beta3 on the cytoplasmic side of the channel. Reason: Supported by structure (Gao 2021, the EXP source), by the absence of any transmembrane segment, and by UniProt's curated subcellular location. Cytoplasm is as precise as the evidence for the free and channel-bound pools combined allows. Supporting Evidence: PMID:34234349 cryo-electron microscopy structures of human Cav2.2 (comprising the core Ξ±1 and the ancillary Ξ±2Ξ΄-1 and Ξ²3 subunits) file:human/CACNB3/CACNB3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:34234349} PMID:25527503 the cytoplasmic Ca V Ξ² auxiliary subunit |
| GO:0005829 cytosol | TAS Reactome:R-HSA-210420 | KEEP AS NON CORE | Summary: Reactome places the beta subunit in the cytosol as part of the presynaptic VGCC influx reaction. Beta3 is a cytosolic protein, but its functional site is the channel complex at the membrane. Reason: Correct as a location of the soluble subunit, but peripheral to its function, which is executed while bound to the cytoplasmic face of the alpha1 subunit (captured by the channel-complex terms). Supporting Evidence: PMID:25527503 the cytoplasmic Ca V Ξ² auxiliary subunit PMID:27481713 an intracellular Ξ² subunit |
| GO:0005891 voltage-gated calcium channel complex | IBA GO_REF:0000033 | ACCEPT | Summary: Beta3 is a subunit of high-voltage-activated CaV1 and CaV2 channel complexes: reconstituted CaV1.3 and CaV2.2 currents (Bell 2001), cryo-EM of human CaV2.2-alpha2delta-1-beta3 (Gao 2021), and the PAINT IBD at the family root node PTN000930213 seeded by beta1-4 orthologs including human CACNB3 itself. Reason: Core cellular component, at the right level of generality because beta3 is found in both L-type (CaV1) and N-type (CaV2.2) complexes; the L-type complex term is accepted separately. Supporting Evidence: PMID:34234349 cryo-electron microscopy structures of human Cav2.2 (comprising the core Ξ±1 and the ancillary Ξ±2Ξ΄-1 and Ξ²3 subunits) PMID:11160515 N-type currents, formed from transiently transfected alpha(1B)/alpha(2)delta-1/beta(3) PMID:11160515 calcium channel currents formed by the human neuronal L-type alpha(1D) subunit, co-expressed with alpha(2)delta-1 and beta(3a) |
| GO:0005891 voltage-gated calcium channel complex | IDA PMID:11160515 Biophysical properties, pharmacology, and modulation of huma... | ACCEPT | Summary: Beta3 is a subunit of high-voltage-activated CaV1 and CaV2 channel complexes: reconstituted CaV1.3 and CaV2.2 currents (Bell 2001), cryo-EM of human CaV2.2-alpha2delta-1-beta3 (Gao 2021), and the PAINT IBD at the family root node PTN000930213 seeded by beta1-4 orthologs including human CACNB3 itself. Reason: Core cellular component, at the right level of generality because beta3 is found in both L-type (CaV1) and N-type (CaV2.2) complexes; the L-type complex term is accepted separately. Supporting Evidence: PMID:34234349 cryo-electron microscopy structures of human Cav2.2 (comprising the core Ξ±1 and the ancillary Ξ±2Ξ΄-1 and Ξ²3 subunits) PMID:11160515 N-type currents, formed from transiently transfected alpha(1B)/alpha(2)delta-1/beta(3) PMID:11160515 calcium channel currents formed by the human neuronal L-type alpha(1D) subunit, co-expressed with alpha(2)delta-1 and beta(3a) |
| GO:0005891 voltage-gated calcium channel complex | IEA GO_REF:0000120 | ACCEPT | Summary: Beta3 is a subunit of high-voltage-activated CaV1 and CaV2 channel complexes: reconstituted CaV1.3 and CaV2.2 currents (Bell 2001), cryo-EM of human CaV2.2-alpha2delta-1-beta3 (Gao 2021), and the PAINT IBD at the family root node PTN000930213 seeded by beta1-4 orthologs including human CACNB3 itself. Reason: Core cellular component, at the right level of generality because beta3 is found in both L-type (CaV1) and N-type (CaV2.2) complexes; the L-type complex term is accepted separately. Supporting Evidence: PMID:34234349 cryo-electron microscopy structures of human Cav2.2 (comprising the core Ξ±1 and the ancillary Ξ±2Ξ΄-1 and Ξ²3 subunits) PMID:11160515 N-type currents, formed from transiently transfected alpha(1B)/alpha(2)delta-1/beta(3) PMID:11160515 calcium channel currents formed by the human neuronal L-type alpha(1D) subunit, co-expressed with alpha(2)delta-1 and beta(3a) |
| GO:0005891 voltage-gated calcium channel complex | TAS PMID:8119293 Cloning, chromosomal location and functional expression of t... | ACCEPT | Summary: Beta3 is a subunit of high-voltage-activated CaV1 and CaV2 channel complexes: reconstituted CaV1.3 and CaV2.2 currents (Bell 2001), cryo-EM of human CaV2.2-alpha2delta-1-beta3 (Gao 2021), and the PAINT IBD at the family root node PTN000930213 seeded by beta1-4 orthologs including human CACNB3 itself. Reason: Core cellular component, at the right level of generality because beta3 is found in both L-type (CaV1) and N-type (CaV2.2) complexes; the L-type complex term is accepted separately. Supporting Evidence: PMID:34234349 cryo-electron microscopy structures of human Cav2.2 (comprising the core Ξ±1 and the ancillary Ξ±2Ξ΄-1 and Ξ²3 subunits) PMID:11160515 N-type currents, formed from transiently transfected alpha(1B)/alpha(2)delta-1/beta(3) PMID:11160515 calcium channel currents formed by the human neuronal L-type alpha(1D) subunit, co-expressed with alpha(2)delta-1 and beta(3a) |
| GO:0006816 calcium ion transport | IBA GO_REF:0000033 | MODIFY | Summary: Beta3 is involved in calcium transport as an auxiliary subunit of high-voltage-activated calcium channel complexes. Reason: True but general. The specific supported process, already annotated to this gene (ISS), is calcium ion transmembrane transport via high voltage-gated calcium channel, an is_a descendant. The IBA at PTN000930213 is sound in placement (all beta paralogs); the refinement is about specificity, not correctness. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000930213 SUPPORTS TRANSFER Family-root node covering all CaVbeta paralogs; human CACNB3 (PTHR11824:SF8) descends from it and is itself an experimental seed. Only the specificity of the term is refined. Proposed replacements: calcium ion transmembrane transport via high voltage-gated calcium channel Supporting Evidence: PMID:11160515 calcium channel currents formed by the human neuronal L-type alpha(1D) subunit, co-expressed with alpha(2)delta-1 and beta(3a) PMID:9751781 in sympathetic beta3-/- neurons, the L- and N-type current was significantly reduced relative to wt |
| GO:0006816 calcium ion transport | IDA PMID:11160515 Biophysical properties, pharmacology, and modulation of huma... | MODIFY | Summary: Beta3 is involved in calcium transport as an auxiliary subunit of high-voltage-activated calcium channel complexes. Reason: True but general. The specific supported process, already annotated to this gene (ISS), is calcium ion transmembrane transport via high voltage-gated calcium channel, an is_a descendant. The IBA at PTN000930213 is sound in placement (all beta paralogs); the refinement is about specificity, not correctness. Proposed replacements: calcium ion transmembrane transport via high voltage-gated calcium channel Supporting Evidence: PMID:11160515 calcium channel currents formed by the human neuronal L-type alpha(1D) subunit, co-expressed with alpha(2)delta-1 and beta(3a) PMID:9751781 in sympathetic beta3-/- neurons, the L- and N-type current was significantly reduced relative to wt |
| GO:0008331 high voltage-gated calcium channel activity | IBA GO_REF:0000033 | MODIFY | Summary: PAINT IBD at the family root (PTN000930213) seeded by a single mouse Cacnb1 annotation. Beta subunits lack a pore; high-voltage-activated channel activity is executed by the alpha1 subunit and modulated by beta. Reason: The node placement is not disputed (all CaVbeta paralogs share the function) but the activity term names the conducting function of the complex rather than what beta3 itself does. The beta3-specific activity is calcium channel regulator activity; the participation in high-voltage-activated transport is captured by GO:0061577 and GO:1901843. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN000930213 SUPPORTS SOURCE BUT NOT TARGET Node seeded by a single mouse Cacnb1 annotation; the inheritance across beta paralogs is sound, but the term names the pore activity of the complex rather than the beta-subunit regulatory activity. Proposed replacements: calcium channel regulator activity Supporting Evidence: PMID:7679112 Coexpression of beta 3 with a cardiac alpha 1 in Xenopus oocytes induces similar changes in Ca2+ channel activity as beta 1 and beta 2, that is, it increases peak currents, modulates the voltage dependence of activation, and accelerates activation file:human/CACNB3/CACNB3-uniprot.txt Regulatory subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents (PubMed:8119293) |
| GO:0016020 membrane | IDA PMID:16525042 Alternative splicing of the voltage-gated Ca2+ channel beta4... | KEEP AS NON CORE | Summary: Beta3 is a peripheral membrane-associated protein via the alpha1 subunit; it has no transmembrane segment. Reason: The cited paper (about the beta4a A domain) is abstract-only here; the curator assigned membrane localization for beta3 from the full text, which we do not overrule. Membrane is as precise as this evidence allows; the informative location is the channel complex. Supporting Evidence: PMID:16525042 Ca2+ channel beta subunits regulate cell-surface expression and gating of voltage-dependent Ca2+ channel alpha1 subunits |
| GO:0030315 T-tubule | IEA GO_REF:0000117 | UNDECIDED | Summary: The skeletal-muscle T-tubule couplon uses beta1a and cardiac dyads mainly beta2; no direct evidence localizing beta3 to T-tubules was found in the cited reviews. Reason: The NAS sources are reviews on CaV1.1/CaV1.2 and alpha2delta; their abstracts do not place beta3 in T-tubules. The ARBA rule is a machine-learned family-level prediction. We cannot verify a beta3-specific T-tubule localization, so neither accept nor remove. Supporting Evidence: PMID:34072954 The number and activity of functional CaV1.2 channels at the t-tubule dyads dictates the amplitude of the Ca2+ influx. PMID:27273705 their ability to reach their required destinations in the cell membrane, their activation and the fine tuning of their biophysical properties are all dramatically influenced by the auxiliary subunits that associate with them |
| GO:0030315 T-tubule | NAS PMID:27273705 Voltage-gated calcium channels and their auxiliary subunits:... | UNDECIDED | Summary: The skeletal-muscle T-tubule couplon uses beta1a and cardiac dyads mainly beta2; no direct evidence localizing beta3 to T-tubules was found in the cited reviews. Reason: The NAS sources are reviews on CaV1.1/CaV1.2 and alpha2delta; their abstracts do not place beta3 in T-tubules. The ARBA rule is a machine-learned family-level prediction. We cannot verify a beta3-specific T-tubule localization, so neither accept nor remove. Supporting Evidence: PMID:34072954 The number and activity of functional CaV1.2 channels at the t-tubule dyads dictates the amplitude of the Ca2+ influx. PMID:27273705 their ability to reach their required destinations in the cell membrane, their activation and the fine tuning of their biophysical properties are all dramatically influenced by the auxiliary subunits that associate with them |
| GO:0045933 positive regulation of muscle contraction | NAS PMID:22982493 Ca(V)1.1: The atypical prototypical voltage-gated CaΒ²βΊ chann... | MARK AS OVER ANNOTATED | Summary: Positive regulation of muscle contraction is a downstream physiological outcome of L-type channel calcium entry, asserted from reviews focused on CaV1.1 (skeletal) and cardiac CaV1.2. Reason: The skeletal and cardiac beta subunits are mainly beta1a and beta2; the cited reviews do not establish a beta3-specific role in contraction. Beta3 regulates the channel, and contraction is an indirect consequence; kept as over-annotation rather than removed because beta3 is expressed in smooth muscle and could contribute in some contexts. Supporting Evidence: PMID:22982493 Ca(V)1.1 is expressed solely in skeletal muscle where it serves multiple purposes; it is the voltage sensor for excitation-contraction coupling PMID:34072954 The number and activity of functional CaV1.2 channels at the t-tubule dyads dictates the amplitude of the Ca2+ influx. |
| GO:0045933 positive regulation of muscle contraction | NAS PMID:34072954 Mechanisms and Regulation of Cardiac Ca(V)1.2 Trafficking. | MARK AS OVER ANNOTATED | Summary: Positive regulation of muscle contraction is a downstream physiological outcome of L-type channel calcium entry, asserted from reviews focused on CaV1.1 (skeletal) and cardiac CaV1.2. Reason: The skeletal and cardiac beta subunits are mainly beta1a and beta2; the cited reviews do not establish a beta3-specific role in contraction. Beta3 regulates the channel, and contraction is an indirect consequence; kept as over-annotation rather than removed because beta3 is expressed in smooth muscle and could contribute in some contexts. Supporting Evidence: PMID:22982493 Ca(V)1.1 is expressed solely in skeletal muscle where it serves multiple purposes; it is the voltage sensor for excitation-contraction coupling PMID:34072954 The number and activity of functional CaV1.2 channels at the t-tubule dyads dictates the amplitude of the Ca2+ influx. |
| GO:0060402 calcium ion transport into cytosol | ISS PMID:25527503 Functional characterization of CaVΞ±2Ξ΄ mutations associated w... | ACCEPT | Summary: Beta3-containing high-voltage-activated channels mediate calcium entry from the extracellular space into the cytosol. Reason: Accurate for the beta3 role as channel subunit; it describes the same influx as GO:0061577 along the destination axis. ISS from rat Cacnb3 (same PANTHER subfamily SF8). Supporting Evidence: PMID:11160515 calcium channel currents formed by the human neuronal L-type alpha(1D) subunit, co-expressed with alpha(2)delta-1 and beta(3a) PMID:12181424 the alpha(2)delta-4 subunit associated with Ca(V)1.2 and beta(3) subunits |
| GO:0061577 calcium ion transmembrane transport via high voltage-gated calcium channel | ISS GO_REF:0000024 | ACCEPT | Summary: Core process: beta3 is a subunit of high-voltage-activated CaV1/CaV2 channels through which calcium crosses the plasma membrane; loss of beta3 reduces neuronal L- and N-type currents. Reason: This is the most specific transport term supported, and the term to which the general calcium transport rows are refined. ISS from rat Cacnb3 (PTHR11824:SF8, same subfamily as human CACNB3) is corroborated by human reconstitution data and mouse knockouts. Supporting Evidence: PMID:11160515 calcium channel currents formed by the human neuronal L-type alpha(1D) subunit, co-expressed with alpha(2)delta-1 and beta(3a) PMID:9751781 in sympathetic beta3-/- neurons, the L- and N-type current was significantly reduced relative to wt PMID:12161429 The molecular mechanism responsible for the phenotype was traced to low expression of N-type calcium channels (alpha1B) |
| GO:0061577 calcium ion transmembrane transport via high voltage-gated calcium channel | ISS PMID:25527503 Functional characterization of CaVΞ±2Ξ΄ mutations associated w... | ACCEPT | Summary: Core process: beta3 is a subunit of high-voltage-activated CaV1/CaV2 channels through which calcium crosses the plasma membrane; loss of beta3 reduces neuronal L- and N-type currents. Reason: This is the most specific transport term supported, and the term to which the general calcium transport rows are refined. ISS from rat Cacnb3 (PTHR11824:SF8, same subfamily as human CACNB3) is corroborated by human reconstitution data and mouse knockouts. Supporting Evidence: PMID:11160515 calcium channel currents formed by the human neuronal L-type alpha(1D) subunit, co-expressed with alpha(2)delta-1 and beta(3a) PMID:9751781 in sympathetic beta3-/- neurons, the L- and N-type current was significantly reduced relative to wt PMID:12161429 The molecular mechanism responsible for the phenotype was traced to low expression of N-type calcium channels (alpha1B) |
| GO:0070588 calcium ion transmembrane transport | IDA PMID:27481713 The Ξ±2Ξ΄-1 subunit remodels CaV1.2 voltage sensors and allows... | MODIFY | Summary: Beta3 participates in transmembrane calcium transport as a subunit of high-voltage-activated channels (shown with human CaV1.2-beta3 in oocytes, Savalli 2016). Reason: True but general; refine to the high-voltage-gated channel-specific descendant already annotated to this gene. Proposed replacements: calcium ion transmembrane transport via high voltage-gated calcium channel Supporting Evidence: PMID:27481713 we expressed in Xenopus oocytes CaV1.2 channels consisting of Ξ±1C and Ξ²3 subunits PMID:12181424 the alpha(2)delta-4 subunit associated with Ca(V)1.2 and beta(3) subunits |
| GO:0070588 calcium ion transmembrane transport | IEA GO_REF:0000002 | MODIFY | Summary: Beta3 participates in transmembrane calcium transport as a subunit of high-voltage-activated channels (shown with human CaV1.2-beta3 in oocytes, Savalli 2016). Reason: True but general; refine to the high-voltage-gated channel-specific descendant already annotated to this gene. Proposed replacements: calcium ion transmembrane transport via high voltage-gated calcium channel Supporting Evidence: PMID:27481713 we expressed in Xenopus oocytes CaV1.2 channels consisting of Ξ±1C and Ξ²3 subunits PMID:12181424 the alpha(2)delta-4 subunit associated with Ca(V)1.2 and beta(3) subunits |
| GO:0070588 calcium ion transmembrane transport | NAS PMID:22982493 Ca(V)1.1: The atypical prototypical voltage-gated CaΒ²βΊ chann... | MODIFY | Summary: Beta3 participates in transmembrane calcium transport as a subunit of high-voltage-activated channels (shown with human CaV1.2-beta3 in oocytes, Savalli 2016). Reason: True but general; refine to the high-voltage-gated channel-specific descendant already annotated to this gene. Proposed replacements: calcium ion transmembrane transport via high voltage-gated calcium channel Supporting Evidence: PMID:27481713 we expressed in Xenopus oocytes CaV1.2 channels consisting of Ξ±1C and Ξ²3 subunits PMID:12181424 the alpha(2)delta-4 subunit associated with Ca(V)1.2 and beta(3) subunits |
| GO:0070588 calcium ion transmembrane transport | NAS PMID:27273705 Voltage-gated calcium channels and their auxiliary subunits:... | MODIFY | Summary: Beta3 participates in transmembrane calcium transport as a subunit of high-voltage-activated channels (shown with human CaV1.2-beta3 in oocytes, Savalli 2016). Reason: True but general; refine to the high-voltage-gated channel-specific descendant already annotated to this gene. Proposed replacements: calcium ion transmembrane transport via high voltage-gated calcium channel Supporting Evidence: PMID:27481713 we expressed in Xenopus oocytes CaV1.2 channels consisting of Ξ±1C and Ξ²3 subunits PMID:12181424 the alpha(2)delta-4 subunit associated with Ca(V)1.2 and beta(3) subunits |
| GO:0072659 protein localization to plasma membrane | ISS PMID:25527503 Functional characterization of CaVΞ±2Ξ΄ mutations associated w... | ACCEPT | Summary: CaVbeta subunits promote surface density of CaV1.2 channels, in part by protecting alpha1 from ubiquitin/proteasome degradation; beta3 knockout lowers N-type channel protein in DRG neurons. Reason: Protein localization to plasma membrane (of the alpha1 partner) is a core, conserved beta-subunit role and is within the beta3 subfamily via the rat ortholog. Supporting Evidence: PMID:25527503 Ca V Ξ² promotes the cell surface density of Ca V 1.2 channels PMID:16525042 Ca2+ channel beta subunits regulate cell-surface expression and gating of voltage-dependent Ca2+ channel alpha1 subunits PMID:12161429 The molecular mechanism responsible for the phenotype was traced to low expression of N-type calcium channels (alpha1B) |
| GO:0098903 regulation of membrane repolarization during action potential | ISS PMID:25527503 Functional characterization of CaVΞ±2Ξ΄ mutations associated w... | MARK AS OVER ANNOTATED | Summary: The source paper reconstituted CaV1.2 with CaVbeta3 and alpha2delta-1 variants associated with short QT; no action potential repolarization was measured for beta3. Reason: Regulation of action potential repolarization is inferred from the disease association of alpha2delta-1 variants, not from a beta3 experiment, and the predominant cardiac beta subunit is beta2. Not removed because L-type current regulation by beta subunits does shape the plateau phase. Supporting Evidence: PMID:25527503 Ca V Ξ² promotes the cell surface density of Ca V 1.2 channels |
| GO:1901843 positive regulation of high voltage-gated calcium channel activity | ISS GO_REF:0000024 | ACCEPT | Summary: Beta3 increases peak current and shifts activation of high-voltage-activated alpha1 subunits (CaV1.2, CaV2.2). Reason: Core regulatory process directly supported by coexpression studies; consistent with the regulator activity term. ISS from rat Cacnb3 within PTHR11824:SF8. Supporting Evidence: PMID:7679112 Coexpression of beta 3 with a cardiac alpha 1 in Xenopus oocytes induces similar changes in Ca2+ channel activity as beta 1 and beta 2, that is, it increases peak currents, modulates the voltage dependence of activation, and accelerates activation file:human/CACNB3/CACNB3-uniprot.txt Regulatory subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents (PubMed:8119293) |
| GO:1990454 L-type voltage-gated calcium channel complex | IPI PMID:27481713 The Ξ±2Ξ΄-1 subunit remodels CaV1.2 voltage sensors and allows... | ACCEPT | Summary: Beta3 assembles with CaV1.2/alpha2delta in L-type complexes: oocyte CaV1.2 (alpha1C + beta3, Savalli 2016), HEK293 CaV1.2/beta3/alpha2delta-4 (Qin 2002), CaV1.3/beta3a (Bell 2001), and cryo-EM of human CaV1.2-beta3-alpha2delta-1. Reason: Well supported; beta3 also occurs in CaV2 (N-type) complexes, which the parent VGCC complex term covers. Supporting Evidence: PMID:27481713 we expressed in Xenopus oocytes CaV1.2 channels consisting of Ξ±1C and Ξ²3 subunits PMID:12181424 the alpha(2)delta-4 subunit associated with Ca(V)1.2 and beta(3) subunits PMID:11160515 calcium channel currents formed by the human neuronal L-type alpha(1D) subunit, co-expressed with alpha(2)delta-1 and beta(3a) |
| GO:1990454 L-type voltage-gated calcium channel complex | ISS GO_REF:0000024 | ACCEPT | Summary: Beta3 assembles with CaV1.2/alpha2delta in L-type complexes: oocyte CaV1.2 (alpha1C + beta3, Savalli 2016), HEK293 CaV1.2/beta3/alpha2delta-4 (Qin 2002), CaV1.3/beta3a (Bell 2001), and cryo-EM of human CaV1.2-beta3-alpha2delta-1. Reason: Well supported; beta3 also occurs in CaV2 (N-type) complexes, which the parent VGCC complex term covers. Supporting Evidence: PMID:27481713 we expressed in Xenopus oocytes CaV1.2 channels consisting of Ξ±1C and Ξ²3 subunits PMID:12181424 the alpha(2)delta-4 subunit associated with Ca(V)1.2 and beta(3) subunits PMID:11160515 calcium channel currents formed by the human neuronal L-type alpha(1D) subunit, co-expressed with alpha(2)delta-1 and beta(3a) |
| GO:1990454 L-type voltage-gated calcium channel complex | ISS GO_REF:0000114 | ACCEPT | Summary: Beta3 assembles with CaV1.2/alpha2delta in L-type complexes: oocyte CaV1.2 (alpha1C + beta3, Savalli 2016), HEK293 CaV1.2/beta3/alpha2delta-4 (Qin 2002), CaV1.3/beta3a (Bell 2001), and cryo-EM of human CaV1.2-beta3-alpha2delta-1. Reason: Well supported; beta3 also occurs in CaV2 (N-type) complexes, which the parent VGCC complex term covers. Supporting Evidence: PMID:27481713 we expressed in Xenopus oocytes CaV1.2 channels consisting of Ξ±1C and Ξ²3 subunits PMID:12181424 the alpha(2)delta-4 subunit associated with Ca(V)1.2 and beta(3) subunits PMID:11160515 calcium channel currents formed by the human neuronal L-type alpha(1D) subunit, co-expressed with alpha(2)delta-1 and beta(3a) |
| GO:1990454 L-type voltage-gated calcium channel complex | ISS PMID:25527503 Functional characterization of CaVΞ±2Ξ΄ mutations associated w... | ACCEPT | Summary: Beta3 assembles with CaV1.2/alpha2delta in L-type complexes: oocyte CaV1.2 (alpha1C + beta3, Savalli 2016), HEK293 CaV1.2/beta3/alpha2delta-4 (Qin 2002), CaV1.3/beta3a (Bell 2001), and cryo-EM of human CaV1.2-beta3-alpha2delta-1. Reason: Well supported; beta3 also occurs in CaV2 (N-type) complexes, which the parent VGCC complex term covers. Supporting Evidence: PMID:27481713 we expressed in Xenopus oocytes CaV1.2 channels consisting of Ξ±1C and Ξ²3 subunits PMID:12181424 the alpha(2)delta-4 subunit associated with Ca(V)1.2 and beta(3) subunits PMID:11160515 calcium channel currents formed by the human neuronal L-type alpha(1D) subunit, co-expressed with alpha(2)delta-1 and beta(3a) |
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Download this section (compressed HTML)Q: Is the channel-independent CaVbeta3-IP3 receptor interaction reported in rodent fibroblasts and beta-cells conserved in human cells, and does it warrant a molecular function annotation distinct from calcium channel regulator activity?
Q: Is there direct evidence placing beta3 (rather than beta1a/beta2) in skeletal or cardiac T-tubule couplons, to resolve the T-tubule annotations?
Experiment: Proximity labelling or co-immunoprecipitation of endogenous CACNB3 with ITPR1-3 in human iPSC-derived neurons or beta-cells, with AID-binding-deficient beta3 mutants, to separate channel-dependent from channel-independent roles.
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