CACNB2 encodes the voltage-dependent L-type calcium channel subunit beta-2 (CaVbeta2), an essential cytosolic auxiliary subunit of high-voltage-activated Ca2+ channels. The protein contains a conserved SH3-HOOK-guanylate kinase (GK) module that binds the alpha-interaction domain (AID) in the I-II linker of the pore-forming alpha1 subunit with nanomolar affinity. CaVbeta2 promotes proper channel trafficking to the plasma membrane and modulates voltage-dependent activation/inactivation kinetics of CaV1.x/CaV2.x channels. Multiple splice variants (beta2a-beta2e) differ in their N-termini, with beta2a being palmitoylated for membrane anchoring and beta2e capable of nuclear translocation. CaVbeta2 also mediates beta-adrenergic regulation of cardiac L-type channels through interaction with the RGK GTPase Rad.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006816 calcium ion transport | IBA GO_REF:0000033 | ACCEPT | Summary: CaVbeta2 is an auxiliary subunit that promotes calcium channel trafficking and modulates channel gating. PMID:1309651 demonstrated that beta2 subunit coexpression is obligatory for functional calcium channel activity, and that it increases peak calcium current. The protein enables calcium ion transport by regulating the alpha1 pore-forming subunit. Reason: IBA annotations for calcium ion transport are appropriate. While CaVbeta2 is not itself the ion pore, it is essential for functional calcium channel expression and directly contributes to calcium transport by enabling channel trafficking to the membrane and modulating channel gating properties [PMID:1309651]. Supporting Evidence: PMID:1309651 the beta 2 subunit appears to serve an obligatory function |
| GO:0005891 voltage-gated calcium channel complex | IBA GO_REF:0000033 | ACCEPT | Summary: CaVbeta2 is a core component of the voltage-gated calcium channel complex, binding the alpha1 subunit AID with nanomolar affinity (6-20 nM) via its GK domain. Structural studies confirm the SH3-GK architecture positions CaVbeta between the AID and VSD-II of the alpha1 subunit. Reason: This is a well-established core function. CaVbeta2 is part of the calcium channel complex in 1:1:1:1 stoichiometry with alpha1, alpha2delta, and gamma subunits [UniProt CC, PMID:1309651]. ComplexPortal entries (CPX-3195 and others) document CACNB2 in multiple CaV1.x channel complexes. Supporting Evidence: PMID:1309651 coexpressed with the beta (beta 2) and the alpha 2 (alpha 2b) subunits |
| GO:0007268 chemical synaptic transmission | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Calcium channels play essential roles in neurotransmitter release at presynaptic terminals. CaVbeta2 is expressed in neurons and contributes to calcium channel function that underlies synaptic transmission. Reason: While L-type calcium channels contribute to synaptic transmission, this is more of a downstream physiological consequence rather than a direct molecular function of CaVbeta2. The primary role of CaVbeta2 is channel assembly and modulation; synaptic transmission is a higher-level process. This annotation is acceptable but represents a non-core function. Supporting Evidence: PMID:8494331 The predicted amino acid sequence of this clone shows a high degree of homology to the beta subunit of calcium channel complexes |
| GO:0098793 presynapse | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Automated inference based on inter-ontology links. CaVbeta2 would be present at presynaptic terminals as part of calcium channel complexes that regulate neurotransmitter release. Reason: Presynaptic localization is consistent with calcium channel function in neurons, but this is based on logical inference rather than direct experimental evidence for CACNB2 specifically. The broader cellular component annotation (voltage-gated calcium channel complex) is more directly supported. Supporting Evidence: file:human/CACNB2/CACNB2-uniprot.txt Expressed in all tissues |
| GO:0099509 regulation of presynaptic cytosolic calcium ion concentration | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Automated inference suggesting CaVbeta2 regulates presynaptic calcium levels through its role in calcium channel function. Reason: This is a reasonable inference but represents a tissue-specific downstream effect rather than a core function. The annotation to GO:0051928 (positive regulation of calcium ion transport) from PMID:1309651 is more directly supported experimentally. Supporting Evidence: GO_REF:0000108 logical inference based on inter-ontology links |
| GO:0005245 voltage-gated calcium channel activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro-based inference. CaVbeta2 does not itself have ion channel activity but is essential for functional channel activity when coexpressed with alpha1. Reason: CaVbeta2 is an auxiliary subunit, not the pore-forming subunit. It does not have intrinsic channel activity. The annotation should reflect its role as a regulator/auxiliary rather than having the activity itself. However, there is an IDA annotation to the same term from PMID:1309651 which is more nuanced. Proposed replacements: voltage-gated calcium channel complex |
| GO:0005262 calcium channel activity | IEA GO_REF:0000043 | MODIFY | Summary: UniProt keyword-based inference. Similar issue as GO:0005245 - CaVbeta2 enables but does not itself possess calcium channel activity. Reason: This annotation conflates the auxiliary subunit with the pore. CaVbeta2 is essential for channel function but the channel activity resides in the alpha1 subunit. A more appropriate annotation would be to the channel complex or a regulatory function. Proposed replacements: voltage-gated calcium channel complex |
| GO:0005891 voltage-gated calcium channel complex | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated annotation confirming CaVbeta2 is part of the voltage-gated calcium channel complex. Reason: This correctly annotates CaVbeta2 as a component of the channel complex, which is well-supported by multiple lines of evidence including structural data and biochemical studies [PMID:1309651, UniProt]. Supporting Evidence: PMID:1309651 coexpression with the alpha 2b subunit |
| GO:0006811 monoatomic ion transport | IEA GO_REF:0000043 | ACCEPT | Summary: General ion transport term from UniProt keyword mapping. Reason: This is a parent term of calcium ion transport (GO:0006816) and is acceptable as a broader annotation. It correctly reflects CaVbeta2's role in enabling calcium channel function. Supporting Evidence: file:human/CACNB2/CACNB2-uniprot.txt Calcium transport keyword |
| GO:0006816 calcium ion transport | IEA GO_REF:0000043 | ACCEPT | Summary: UniProt keyword-based inference for calcium ion transport, consistent with the IBA annotation to the same term. Reason: Consistent with the IBA annotation and well-supported by the role of CaVbeta2 in enabling functional calcium channel expression [PMID:1309651]. Supporting Evidence: file:human/CACNB2/CACNB2-uniprot.txt Calcium channel; Calcium transport keywords |
| GO:0034220 monoatomic ion transmembrane transport | IEA GO_REF:0000043 | ACCEPT | Summary: UniProt keyword-based inference for ion transmembrane transport. Reason: Appropriate parent term reflecting CaVbeta2's role in enabling calcium flux across the plasma membrane through the channel complex. Supporting Evidence: file:human/CACNB2/CACNB2-uniprot.txt Ion transport keyword |
| GO:0034702 monoatomic ion channel complex | IEA GO_REF:0000043 | ACCEPT | Summary: UniProt keyword-based inference for ion channel complex membership. Reason: Correct parent term of GO:0005891 (voltage-gated calcium channel complex). CaVbeta2 is indeed part of an ion channel complex. Supporting Evidence: file:human/CACNB2/CACNB2-uniprot.txt Ion channel keyword |
| GO:0042383 sarcolemma | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location-based inference for sarcolemma localization. UniProt explicitly states CaVbeta2 localizes to sarcolemma in cardiac muscle. Reason: This is directly supported by UniProt subcellular location annotation stating "Cell membrane, sarcolemma; Peripheral membrane protein; Cytoplasmic side." CaVbeta2 associates with L-type channels in cardiac T-tubule/sarcolemma. Supporting Evidence: file:human/CACNB2/CACNB2-uniprot.txt Cell membrane, sarcolemma; Peripheral membrane protein; Cytoplasmic side |
| GO:0070588 calcium ion transmembrane transport | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated inference for calcium ion transmembrane transport. Reason: Consistent with CaVbeta2's essential role in enabling functional calcium channel activity that mediates transmembrane calcium flux. Supporting Evidence: PMID:1309651 directs the recombinant expression of a dihydropyridine-sensitive L-type Ca2+ channel |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: High-throughput protein interactome study (HuRI) identified binary protein interactions involving CACNB2. Reason: While technically correct, "protein binding" is uninformative. CaVbeta2 binds specific proteins including the alpha1 subunit AID, RRAD, CAMK2A, and others. More specific binding annotations would be more informative. Supporting Evidence: PMID:32296183 With approximately 53,000 protein-protein interactions, HuRI has approximately four times as many such interactions as there are high-quality curated interactions from small-scale studies |
| GO:0051015 actin filament binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara ortholog transfer suggesting actin filament binding. PMID:25533460 demonstrated direct CaVbeta-actin interaction. Reason: PMID:25533460 provides experimental evidence for direct CaVbeta-actin interaction using co-sedimentation and FRET experiments. The study showed CaVbeta2 distributes along actin filaments in cardiomyocytes. Supporting Evidence: PMID:25533460 we uncover a direct interaction between CaVbeta and actin filaments |
| GO:0098684 photoreceptor ribbon synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara ortholog transfer suggesting localization to photoreceptor ribbon synapse. The beta2e isoform is known to predominate in retina. Reason: The beta2e isoform is specifically expressed in retina, making this a plausible but tissue-specific localization. The deep research file notes "beta2e predominates in retina." However, this is based on ortholog transfer rather than direct experimental evidence in human. Supporting Evidence: file:human/CACNB2/CACNB2-deep-research-falcon.md beta2e predominates in retina |
| GO:0099626 voltage-gated calcium channel activity involved in regulation of presynaptic cytosolic calcium levels | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl Compara ortholog transfer for presynaptic calcium channel activity. Reason: CaVbeta2 is not the pore and does not have intrinsic channel activity. This annotation conflates the auxiliary subunit with the functional activity. The annotation should be to the complex or a regulatory function. Proposed replacements: voltage-gated calcium channel complex |
| GO:0070588 calcium ion transmembrane transport | NAS PMID:22982493 Ca(V)1.1: The atypical prototypical voltage-gated CaΒ²βΊ chann... | ACCEPT | Summary: Non-traceable author statement from a review about CaV1.1 channels noting the general role of beta subunits in calcium channel function. Reason: While NAS is a weaker evidence code, the annotation is consistent with the established role of CaVbeta2. PMID:22982493 is a review discussing calcium channel function. Supporting Evidence: PMID:22982493 Ca(V)1.1 is the prototype for the other nine known Ca(V) channel isoforms |
| GO:0030315 T-tubule | NAS PMID:27273705 Voltage-gated calcium channels and their auxiliary subunits:... | ACCEPT | Summary: Non-traceable author statement from Dolphin review on voltage-gated calcium channels and their auxiliary subunits, indicating T-tubule localization. Reason: T-tubule localization is consistent with the role of L-type calcium channels in excitation-contraction coupling in cardiac and skeletal muscle. The review discusses calcium channel physiology and pathophysiology. Supporting Evidence: PMID:27273705 Voltage-gated calcium channels and their auxiliary subunits |
| GO:0045933 positive regulation of muscle contraction | NAS PMID:22982493 Ca(V)1.1: The atypical prototypical voltage-gated CaΒ²βΊ chann... | KEEP AS NON CORE | Summary: CaVbeta2 contributes to calcium influx that triggers muscle contraction. Reason: This is a downstream physiological effect. CaVbeta2 enables calcium channel function, and calcium influx is required for muscle contraction, but this is an indirect effect rather than a direct molecular function. Supporting Evidence: PMID:22982493 Ca(V)1.1 is the prototype for the other nine known Ca(V) channel isoforms |
| GO:0045933 positive regulation of muscle contraction | NAS PMID:34072954 Mechanisms and Regulation of Cardiac Ca(V)1.2 Trafficking. | KEEP AS NON CORE | Summary: Review on CaV1.2 trafficking mechanisms discussing the role of beta subunits in cardiac calcium channel function. Reason: Consistent with the other NAS annotation to this term. CaVbeta2 contributes to cardiac calcium channel function which underlies muscle contraction, but this is an indirect downstream effect. 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 |
| GO:0070588 calcium ion transmembrane transport | NAS PMID:27273705 Voltage-gated calcium channels and their auxiliary subunits:... | ACCEPT | Summary: Non-traceable author statement from Dolphin review on voltage-gated calcium channels. Reason: Consistent with other annotations and the established role of CaVbeta2 in enabling functional calcium channel activity. Supporting Evidence: PMID:27273705 For the CaV 1 and CaV 2 channels, their ability to reach their required destinations in the cell membrane |
| GO:0005515 protein binding | IPI PMID:28130356 A Novel Human CAMK2A Mutation Disrupts Dendritic Morphology ... | MARK AS OVER ANNOTATED | Summary: Study on CAMK2A mutations and ASD-related behaviors identified interaction between CaMKIIalpha and CACNB2. The E183V mutation reduced CaMKIIalpha binding to calcium channel subunits. Reason: The study identifies specific interaction with CAMK2A but the annotation is to generic "protein binding." UniProt confirms CACNB2 interacts with CAMK2A. A more specific annotation would be preferable. Supporting Evidence: PMID:28130356 The E183V mutation also reduces CaMKIIalpha binding to established ASD-linked proteins, such as Shank3 and subunits of l-type calcium channels |
| GO:0005891 voltage-gated calcium channel complex | IDA PMID:17224476 Loss-of-function mutations in the cardiac calcium channel un... | ACCEPT | Summary: Antzelevitch et al. studied loss-of-function mutations in cardiac calcium channels including CACNB2 (S481L mutation). CHO-K1 cells were cotransfected with CACNB2b and other channel subunits for electrophysiology studies. Reason: The study directly demonstrates CaVbeta2b is part of the cardiac L-type calcium channel complex through heterologous expression and electrophysiology. Mutations in CACNB2 affect channel function. Supporting Evidence: PMID:17224476 CHO-K1 cells were cotransfected with cDNAs encoding wild-type or mutant CACNB2b |
| GO:0051015 actin filament binding | ISS PMID:25533460 Direct interaction of CaVΞ² with actin up-regulates L-type ca... | ACCEPT | Summary: Study demonstrated direct CaVbeta-actin interaction using co-sedimentation assays and FRET experiments in HL-1 cardiomyocytes. Single-molecule localization showed CaVbeta2 distributing along actin filaments. Reason: This is strong experimental evidence for actin filament binding. The study used multiple methods to demonstrate the interaction and showed functional relevance for channel trafficking. Supporting Evidence: PMID:25533460 using co-sedimentation assays and FRET experiments, we uncover a direct interaction between CaVbeta and actin filaments |
| GO:0072659 protein localization to plasma membrane | ISS PMID:25533460 Direct interaction of CaVΞ² with actin up-regulates L-type ca... | ACCEPT | Summary: The study demonstrated that CaVbeta promotes anterograde trafficking of L-type channels by anchoring them to actin filaments en route to the plasma membrane. Reason: The study provides a model where CaVbeta promotes channel trafficking to the membrane via actin interaction. This is consistent with the known role of CaVbeta2 in channel trafficking. Supporting Evidence: PMID:25533460 CaVbeta promotes anterograde trafficking of the L-type channels by anchoring them to actin filaments in their itinerary to the plasma membrane |
| GO:0086007 voltage-gated calcium channel activity involved in cardiac muscle cell action potential | IMP PMID:17224476 Loss-of-function mutations in the cardiac calcium channel un... | MODIFY | Summary: Study identified CACNB2 mutations in Brugada syndrome patients with cardiac arrhythmias. The S481L mutation caused loss-of-function affecting cardiac action potentials. Reason: CaVbeta2 does not have intrinsic channel activity - it is an auxiliary subunit. The annotation should reflect its role in modulating channel function. The correct annotation would be to a regulatory function or the channel complex. Proposed replacements: voltage-gated calcium channel complex Supporting Evidence: PMID:17224476 loss-of-function missense mutations in CACNA1C (A39V and G490R) and CACNB2 (S481L) encoding the alpha1- and beta2b-subunits |
| GO:0086045 membrane depolarization during AV node cell action potential | IMP PMID:17224476 Loss-of-function mutations in the cardiac calcium channel un... | KEEP AS NON CORE | Summary: Study on Brugada syndrome with CACNB2 mutations affecting cardiac conduction. Reason: This is a specific cardiac electrophysiology phenotype associated with CACNB2 mutations. While the annotation captures the disease phenotype, membrane depolarization is a downstream effect of calcium channel function rather than a direct function of CaVbeta2. Supporting Evidence: PMID:17224476 Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation |
| GO:0086056 voltage-gated calcium channel activity involved in AV node cell action potential | IMP PMID:17224476 Loss-of-function mutations in the cardiac calcium channel un... | MODIFY | Summary: Study linking CACNB2 mutations to cardiac arrhythmias affecting AV node function. Reason: Same issue as GO:0086007 - CaVbeta2 is not the channel pore and does not have intrinsic channel activity. It modulates channel function as an auxiliary subunit. Proposed replacements: voltage-gated calcium channel complex Supporting Evidence: PMID:17224476 ST-segment elevation, short QT intervals, and sudden cardiac death |
| GO:0086091 regulation of heart rate by cardiac conduction | IMP PMID:17224476 Loss-of-function mutations in the cardiac calcium channel un... | KEEP AS NON CORE | Summary: CACNB2 mutations cause cardiac arrhythmias affecting heart rate and conduction. Reason: This is a downstream physiological effect of calcium channel dysfunction. CaVbeta2 contributes to cardiac calcium channel function which is essential for proper conduction and heart rate, but this is an indirect effect. Supporting Evidence: PMID:17224476 Brugada syndrome phenotype is combined with shorter-than-normal QT intervals |
| GO:0098912 membrane depolarization during atrial cardiac muscle cell action potential | IMP PMID:17224476 Loss-of-function mutations in the cardiac calcium channel un... | KEEP AS NON CORE | Summary: Brugada syndrome study showing effects of CACNB2 mutations on atrial action potentials. Reason: Similar to other cardiac electrophysiology annotations - this is a downstream consequence of calcium channel function rather than a direct molecular function. Supporting Evidence: PMID:17224476 cardiac calcium channel underlie a new clinical entity |
| GO:1904879 positive regulation of calcium ion transmembrane transport via high voltage-gated calcium channel | ISS PMID:25533460 Direct interaction of CaVΞ² with actin up-regulates L-type ca... | ACCEPT | Summary: Study demonstrated that CaVbeta2 overexpression increases L-type current by increasing channels in the plasma membrane. Reason: This accurately reflects the role of CaVbeta2 in promoting calcium channel trafficking and increasing calcium current. The study showed CaVbeta2-N3 overexpression induced an increase in L-type current. Supporting Evidence: PMID:25533460 Overexpression of CaVbeta2-N3 in HL-1 cells induces an increase in L-type current without altering voltage-dependent activation, thus reflecting an increased number of channels in the plasma membrane |
| GO:1990454 L-type voltage-gated calcium channel complex | IDA PMID:1309651 Structure and functional expression of alpha 1, alpha 2, and... | ACCEPT | Summary: Williams et al. demonstrated functional expression of L-type calcium channels requiring coexpression of beta2 with alpha1D and alpha2b subunits in Xenopus oocytes. Reason: This is a core annotation strongly supported by the paper. The study showed beta2 is required for functional L-type channel expression and is part of the channel complex. Supporting Evidence: PMID:1309651 directs the recombinant expression of a dihydropyridine-sensitive L-type Ca2+ channel when coexpressed with the beta (beta 2) and the alpha 2 (alpha 2b) subunits |
| GO:0008331 high voltage-gated calcium channel activity | IDA PMID:1309651 Structure and functional expression of alpha 1, alpha 2, and... | MODIFY | Summary: The study expressed a human neuronal high-voltage-activated calcium channel requiring beta2 for function. Reason: CaVbeta2 enables high-voltage-gated calcium channel function but does not itself have channel activity. The alpha1 subunit forms the pore. The annotation should reflect the auxiliary/regulatory role. Proposed replacements: L-type voltage-gated calcium channel complex Supporting Evidence: PMID:1309651 the beta 2 subunit appears to serve an obligatory function |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5577213 | ACCEPT | Summary: Reactome pathway entry for LTCC multimer transporting calcium from extracellular region to cytosol places CaVbeta2 at the plasma membrane. Reason: CaVbeta2 localizes to the plasma membrane as part of the L-type calcium channel complex. UniProt also states sarcolemma/plasma membrane localization. Supporting Evidence: file:human/CACNB2/CACNB2-uniprot.txt Cell membrane, sarcolemma; Peripheral membrane protein; Cytoplasmic side |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9614031 | ACCEPT | Summary: Reactome pathway for Class IV antihypertensives binding LTCC multimer. Reason: Same as above - plasma membrane localization is well-established for CaVbeta2. Supporting Evidence: Reactome:R-HSA-9614031 Class IV antihypertensives bind LTCC multimer |
| GO:0051928 positive regulation of calcium ion transport | IDA PMID:1309651 Structure and functional expression of alpha 1, alpha 2, and... | ACCEPT | Summary: Williams et al. showed that beta2 coexpression is required for functional calcium channel expression and increases peak calcium current. Reason: This is a core function. The study demonstrated that "the beta 2 subunit appears to serve an obligatory function" and that channels with beta2 have enhanced calcium current compared to alpha1 alone (which showed no current). Supporting Evidence: PMID:1309651 Expression of the alpha 1D subunit alone, or coexpression with the alpha 2b subunit, did not elicit functional Ca2+ channel activity. Thus, the beta 2 subunit appears to serve an obligatory function |
| GO:0005245 voltage-gated calcium channel activity | IDA PMID:1309651 Structure and functional expression of alpha 1, alpha 2, and... | MODIFY | Summary: Study demonstrated voltage-gated calcium channel activity requires beta2. Reason: While the study demonstrates CaVbeta2 is essential for channel function, CaVbeta2 itself does not have ion channel activity - the alpha1 subunit forms the pore. The annotation should reflect the regulatory role. Proposed replacements: voltage-gated calcium channel complex Supporting Evidence: PMID:1309651 the beta 2 subunit appears to serve an obligatory function |
| GO:0070509 calcium ion import | IDA PMID:1309651 Structure and functional expression of alpha 1, alpha 2, and... | ACCEPT | Summary: Study demonstrated functional calcium influx through channels containing beta2. Reason: CaVbeta2 enables calcium ion import by being essential for functional channel expression. The term correctly reflects the biological process. Supporting Evidence: PMID:1309651 dihydropyridine-sensitive L-type Ca2+ channel |
| GO:0005515 protein binding | IPI PMID:17525370 Dominant negative suppression of Rad leads to QT prolongatio... | MODIFY | Summary: Study demonstrated CACNB2 interaction with RRAD (Ras associated with diabetes), an RGK GTPase that regulates L-type calcium channel function. Reason: The study identifies a specific interaction with RRAD that is functionally important for channel trafficking. "Protein binding" is too generic; a more specific annotation would be preferable. Proposed replacements: protein binding Supporting Evidence: PMID:17525370 upregulation of L-type Ca2+ channel expression in the plasma membrane file:human/CACNB2/CACNB2-uniprot.txt Interacts with RRAD; interaction may be involved in beta-adrenergic regulation of heart rate and contractile force |
| GO:0007528 neuromuscular junction development | TAS PMID:8494331 Cloning and characterization of a Lambert-Eaton myasthenic s... | KEEP AS NON CORE | Summary: Rosenfeld et al. identified CACNB2 (MysB) as a Lambert-Eaton myasthenic syndrome antigen with homology to calcium channel beta subunits. The syndrome affects the neuromuscular junction. Reason: While CaVbeta2 is implicated in Lambert-Eaton syndrome affecting the NMJ, this annotation represents disease involvement rather than a normal developmental function. The study cloned the antigen but did not directly demonstrate a role in NMJ development. Supporting Evidence: PMID:8494331 Lambert-Eaton myasthenic syndrome is a paraneoplastic neuromuscular disorder in which an immune response directed against a small-cell lung tumor crossreacts with antigens in the neuromuscular junction |
| GO:0005262 calcium channel activity | NAS PMID:9594024 Effects of temperature on human L-type cardiac Ca2+ channels... | MODIFY | Summary: Allen and Mikala studied temperature effects on L-type cardiac calcium channels expressed in Xenopus oocytes using different beta subunit isoforms. Reason: CaVbeta2 is an auxiliary subunit that modulates channel properties but does not itself have channel activity. The alpha1 subunit forms the pore. Proposed replacements: voltage-gated calcium channel complex Supporting Evidence: PMID:9594024 Using instead a different CaCh beta subunit isoform, beta2c |
| GO:0005886 plasma membrane | NAS PMID:9594024 Effects of temperature on human L-type cardiac Ca2+ channels... | ACCEPT | Summary: Study expressed calcium channels at the plasma membrane of Xenopus oocytes using various subunit combinations. Reason: Plasma membrane localization is well-established and consistent with the function of CaVbeta2 as part of the calcium channel complex at the cell surface. Supporting Evidence: PMID:9594024 cloned human cardiac CaChs expressed in Xenopus oocytes |
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Download this section (compressed HTML)Q: What is the relative contribution of different CaVbeta2 isoforms (beta2a-e) to channel function in different tissues? The isoforms differ in N-terminal sequences affecting membrane association (palmitoylation for beta2a, nuclear translocation for beta2e). Understanding tissue-specific isoform functions could clarify disease mechanisms.
Q: How does the CaVbeta2-RRAD interaction modulate beta-adrenergic regulation of cardiac calcium channels at the molecular level? Recent work (PMID:36424916) showed Rad phosphorylation releases CaVbeta-mediated inhibition. The structural basis of this regulation is not fully understood.
Experiment: Cryo-EM structural determination of full L-type calcium channel complex with different CaVbeta2 isoforms to understand isoform-specific contributions. While structures exist, comparing different beta2 isoforms could reveal how N-terminal differences affect channel architecture and gating.
Experiment: Live-cell imaging of CaVbeta2e nuclear translocation dynamics and identification of nuclear target genes. The beta2e isoform can translocate to the nucleus and regulate gene expression (Frontiers in Physiology 2025), but the target genes are not well characterized.
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