CACNA1B encodes the pore-forming alpha1B subunit of the N-type, high-voltage-activated calcium channel CaV2.2. Its four homologous transmembrane repeats form voltage sensors and a calcium-selective pore. In neuronal plasma membranes, depolarization opens the channel and calcium entry couples electrical activity to neurotransmitter release. Beta and alpha2delta auxiliary subunits influence channel expression and gating, while presynaptic partners and phosphorylation pathways regulate the alpha1B subunit. The channel is sensitive to omega-conotoxins, including the pore blocker ziconotide. Biallelic variants predicted to cause loss of function underlie autosomal recessive neurodevelopmental disorder with seizures and non-epileptic hyperkinetic movements (NEDNEH); impaired calcium influx and synaptic transmission are the proposed disease mechanism.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001540 amyloid-beta binding | IC PMID:23376566 Synthetic AΞ² oligomers (AΞ²(1-42) globulomer) modulate presyn... | UNDECIDED | Summary: Amyloid-beta modulates channel activity, while a physical binding assertion remains unresolved. Reason: PMID:23376566 reports modulation of recombinant N-type currents and prevention of oligomer-induced synaptic deficits by channel blockers. The complete cached abstract and accessible indexed primary Results/conclusion do not establish the particular physical interaction required by GO:0001540. The original IC inference from modulation of synaptic transmission and response to amyloid-beta is preserved. Full target binding assays or supplementary experiments were not inspected; this is an access-bounded uncertainty, not a claim that binding is false. Functional modulation alone is not equated with a demonstrated ligand-binding site. Supporting Evidence: |
| GO:0005216 monoatomic ion channel activity | IEA GO_REF:0000002 | MODIFY | Summary: The broad ion-channel assignment can be refined to the established high-voltage calcium-channel activity. Reason: The InterPro channel-domain inference is sound but broad. Direct recombinant human alpha1B expression in PMID:1321501 and the human CaV2.2 structure in PMID:34234349 establish the more informative N-type high-voltage calcium-channel activity already represented among the existing annotations. This refines the same pore function without adding a redundant new assertion. Proposed replacements: high voltage-gated calcium channel activity |
| GO:0005245 voltage-gated calcium channel activity | IDA PMID:1321501 Structure and functional expression of an omega-conotoxin-se... | ACCEPT | Summary: Human alpha1B forms a functional voltage-gated N-type calcium channel. Reason: The complete PMID:1321501 abstract explicitly describes human alpha1B-1 coexpression with human beta2 and alpha2b in HEK293 cells and the resulting omega-conotoxin-sensitive, dihydropyridine-insensitive channel activity. Alpha1B forms the pore; auxiliary-subunit requirements do not transfer that pore activity to the auxiliary proteins. The full paper and individual traces were not inspected. Supporting Evidence: PMID:1321501 recombinant expression of N-type calcium channel activity |
| GO:0005245 voltage-gated calcium channel activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined sequence annotations correctly identify a voltage-gated calcium channel. Reason: The ARBA/InterPro source assignment agrees with independently characterized human alpha1B channel activity and structure. It describes the channel itself, rather than a calcium-channel regulator. The individual rule derivations were not re-created, and the source identifiers remain unchanged. |
| GO:0005245 voltage-gated calcium channel activity | IMP PMID:25296916 CACNA1B mutation is linked to unique myoclonus-dystonia synd... | ACCEPT | Summary: Electrophysiology of WT and R1389H channels supports calcium-channel activity. Reason: The complete PMID:25296916 abstract reports whole-cell and single-channel recordings, with lower open-channel current in R1389H and preserved selectivity and voltage-dependent activation/inactivation. These observations support the existing molecular function independently of the paper's proposed disease causality. The latter was challenged by the later cohort cited in UniProt and independently checked through its official abstract, as documented in the notes; functional current measurements are not discarded because a genetic association is disputed. Supporting Evidence: PMID:25296916 when open, R1389H CaV2.2 channels carried less current compared with WT channels file:human/CACNA1B/CACNA1B-uniprot.txt |
| GO:0005245 voltage-gated calcium channel activity | TAS PMID:1321501 Structure and functional expression of an omega-conotoxin-se... | ACCEPT | Summary: The stated N-type calcium-channel function is experimentally grounded. Reason: PMID:1321501 directly reports recombinant expression of the human N-type channel and establishes the same function cited by this TAS annotation. Retain both original evidence records; duplicated terms with different evidence codes are legitimate. Supporting Evidence: |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Calcium interaction is a feature of the calcium-conducting pore. Reason: The source EF-hand-domain mapping is retained at its broad calcium-binding scope. Independently, the authenticated fuller PMID:34234349 source resolves calcium coordinated by the four glutamates of the alpha1B selectivity filter; the normal canonical cache is abstract-only, and the supplemental reading boundary is recorded in the reference assessment and notes. This corroborates calcium interaction by the target without establishing a separate soluble calcium-sensor activity or validating a particular EF-hand affinity. Ion binding is incorporated within the channel core. |
| GO:0005515 protein binding | IPI PMID:11438518 Direct interaction of the Rab3 effector RIM with Ca2+ channe... | KEEP AS NON CORE | Summary: RIM C2 domains bind the alpha1B channel subunit. Reason: The complete PMID:11438518 abstract explicitly reports calcium-independent binding of RIM C2A and C2B domains to alpha1B. The exact source partner is UniProtKB:Q86UR5, and the CACNA1B UniProt record independently lists RIMS1 interaction. Retain this supported generic interaction as non-core under the project policy. The cached paper is abstract-only; organism-specific constructs, domain-assay details and intact-channel versus fragment conditions were not verified from its full text. RIM scaffold activity must not be transferred to the channel. Supporting Evidence: PMID:11438518 RIM-C(2)A and RIM-C(2)B bind in a Ca(2+)-independent manner to alpha1B file:human/CACNA1B/CACNA1B-uniprot.txt |
| GO:0005515 protein binding | IPI PMID:15728831 A protein phosphatase 2calpha-Ca2+ channel complex for depho... | MODIFY | Summary: Alpha1B binds the protein phosphatase PPM1A through its intracellular C terminus. Reason: The actual PMID:15728831 Methods and Results describe human alpha1B C-terminal bait, rat-brain prey, recombinant pulldown and HEK293 coimmunoprecipitation, with native rat-brain association providing additional context. The exact xenologous P20650 Ppm1a source partner is preserved. Official GO:0019903 specifically covers binding to a protein phosphatase, so it refines the generic term without attributing dephosphorylation or phosphatase activation to CACNA1B. Alpha1B is the phosphatase-associated channel substrate. The binding is a regulatory feature of the channel, not a separate catalytic core. Proposed replacements: protein phosphatase binding Supporting Evidence: PMID:15728831 Binding of PP2cΞ± to NCF was verified by GST-fusion protein pulldown assays file:human/CACNA1B/CACNA1B-uniprot.txt |
| GO:0005515 protein binding | IPI PMID:20195357 A comprehensive resource of interacting protein regions for ... | KEEP AS NON CORE | Summary: A curated CACNA1BβRXRB interaction is retained with screen-specific access limits. Reason: The exact IPI partner UniProtKB:P28702 corresponds to the Q00975βP28702 RXRB interaction explicitly present in the CACNA1B UniProt record, with three curated experiments. PMID:20195357 is a human mRNA-display interaction-region screen; its complete abstract and actual methodological narrative were read, including human brain prey and fragment-based screening. The CACNA1BβRXRB supplemental row and individual verification status were not inspected. Retain the supported generic association as non-core with curator deference to the reconciled exact edge; do not claim independently verified full-length binary binding, physiological nuclear localization, or transcriptional activity. The transcription-factor foreground is not evidence that this annotation is miscited. Supporting Evidence: PMID:20195357 large-scale IR data set obtained using mRNA display file:human/CACNA1B/CACNA1B-uniprot.txt |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-210420 | ACCEPT | Summary: CaV2.2 conducts calcium across the neuronal plasma membrane. Reason: The complete cached Reactome entry describes voltage-dependent presynaptic calcium influx. Its event summary supplies reaction context; the preserved Reactome-derived GOA assertion supplies the compartment assignment. Recombinant channel electrophysiology and UniProt independently corroborate the plasma-membrane location, without claiming that the event text contains a separate compartment field. |
| GO:0005891 voltage-gated calcium channel complex | IBA GO_REF:0000033 | ACCEPT | Summary: Alpha1B is the pore-forming component of a voltage-gated calcium-channel complex. Reason: The PAINT assertion through PTN001295293 is consistent with target human alpha1B assembled with beta and alpha2delta subunits in PMID:1321501 and PMID:34234349. The exact phylogenetic node placement was not independently reconstructed; neither donor count nor a mixed homolog list is treated as evidence of a propagation defect. |
| GO:0005891 voltage-gated calcium channel complex | IEA GO_REF:0000002 | ACCEPT | Summary: Channel-domain annotation correctly places alpha1B in the calcium-channel complex. Reason: The InterPro-based complex-membership inference agrees with the directly reconstituted human channel and its cryo-EM structure. The alpha1B subunit forms the pore within this complex; no separate auxiliary-subunit identity is assigned to it. |
| GO:0005891 voltage-gated calcium channel complex | TAS PMID:1321501 Structure and functional expression of an omega-conotoxin-se... | ACCEPT | Summary: Human alpha1B forms a functional complex with auxiliary channel subunits. Reason: The complete PMID:1321501 abstract reports coexpression with human beta2 and alpha2b. Beta2 was necessary for channel activity under those experimental conditions, while alpha2b modulated channel expression. Retain the complex annotation without claiming that this particular auxiliary-subunit combination is invariant in every neuron. Supporting Evidence: PMID:1321501 beta 2 subunit was necessary for N-type channel activity |
| GO:0006811 monoatomic ion transport | IEA GO_REF:0000002 | MODIFY | Summary: The broad ion-transport inference can be refined to calcium import across the plasma membrane. Reason: Human alpha1B is the ion-conducting pore for inward calcium current. The official GO:0098703 definition describes movement of calcium from outside the cell across the plasma membrane into the cytosol, matching this mechanism and an existing target IBA annotation. This refines the broad source term using target channel evidence rather than proposing a new transport process. Proposed replacements: calcium ion import across plasma membrane |
| GO:0007268 chemical synaptic transmission | IBA GO_REF:0000033 | ACCEPT | Summary: Presynaptic calcium influx through CaV2.2 participates directly in chemical synaptic transmission. Reason: The conserved PAINT assertion through PTN000004141 is supported independently by the target channel's calcium-conducting role and pharmacological modulation of synaptic transmission in PMID:23376566. Calcium entry is the step performed by alpha1B; vesicle fusion is downstream. The family node was not independently reconstructed, and no adverse inference is drawn from donor number or species. Supporting Evidence: GO_REF:0000033 file:human/CACNA1B/CACNA1B-uniprot.txt |
| GO:0007268 chemical synaptic transmission | TAS PMID:9030575 Isolation and characterization of the 5'-upstream region of ... | ACCEPT | Summary: The stated chemical-synaptic-transmission role is consistent with independently established channel function. Reason: PMID:9030575 primarily assays the human CACNA1B promoter and its neuronal reporter expression, not an isolated neurotransmitter-release experiment. Its TAS assertion is retained by curator deference with independent channel-expression, synaptic pharmacology and UniProt evidence. The promoter study does not assign transcription-factor activity to the channel. |
| GO:0008331 high voltage-gated calcium channel activity | IBA GO_REF:0000033 | ACCEPT | Summary: The conserved high-voltage calcium-channel function captures the N-type pore activity. Reason: The PTN001295293 PAINT inference agrees with human recombinant channel expression and structure. The target Q00975 appearing in WITH/FROM represents legitimate descendant experimental grounding, not circularity. N-type channels are included within the verified GO:0008331 definition. Exact PAINT node placement was not independently inspected, but no target-specific loss or functional divergence is evident from the direct evidence. |
| GO:0008331 high voltage-gated calcium channel activity | IMP PMID:23376566 Synthetic AΞ² oligomers (AΞ²(1-42) globulomer) modulate presyn... | ACCEPT | Summary: Recombinant N-type current modulation supports high-voltage calcium-channel activity. Reason: PMID:23376566 directly records recombinant presynaptic calcium currents in HEK293 cells and a shift of N-type voltage activation after synthetic amyloid-beta globulomer application. This supports the channel activity while leaving the separate physical amyloid-binding assertion unresolved. Human alpha1B function is independently established by PMID:1321501; the abstract does not identify every construct sequence used in the 2013 assay. Supporting Evidence: PMID:23376566 N-type calcium channels to more hyperpolarized values |
| GO:0016020 membrane | EXP PMID:34234349 Structure of human Ca(v)2.2 channel blocked by the painkille... | MODIFY | Summary: The broad membrane location can be refined to plasma membrane. Reason: The preserved source asserts membrane association. Human alpha1B recombinant electrophysiology and curated target localization establish plasma membrane more specifically. PMID:34234349 supplies transmembrane channel architecture from a purified human alpha1B/alpha2delta1/beta3 complex; the detergent-purified structure alone is not an endogenous localization experiment. Refinement therefore uses the combined target evidence, without inferring a particular presynaptic subdomain from the cryo-EM preparation. Proposed replacements: plasma membrane Supporting Evidence: PMID:34234349 cryo-electron microscopy structures of human Cav2.2 file:human/CACNA1B/CACNA1B-uniprot.txt |
| GO:0016020 membrane | IEA GO_REF:0000120 | MODIFY | Summary: The broad membrane location can be refined to plasma membrane. Reason: The preserved source asserts membrane association. Human alpha1B recombinant electrophysiology and curated target localization establish plasma membrane more specifically. PMID:34234349 supplies transmembrane channel architecture from a purified human alpha1B/alpha2delta1/beta3 complex; the detergent-purified structure alone is not an endogenous localization experiment. Refinement therefore uses the combined target evidence, without inferring a particular presynaptic subdomain from the cryo-EM preparation. Proposed replacements: plasma membrane |
| GO:0043025 neuronal cell body | IBA GO_REF:0000033 | ACCEPT | Summary: A neuronal cell-body pool is consistent with the conserved channel distribution. Reason: Retain the PTN000004144 PAINT cellular-location assertion by curator deference and corroborating curated neuronal/somatic channel distribution. The rat ortholog Q02294 record independently describes somatic as well as terminal function. Exact PAINT placement and a human endogenous cell-body localization assay were not independently inspected; expression in heterologous cells is not substituted for such an assay. PMID:30982612 adds human regional CNS expression context, but its Figure S4 evidence concerns tissue mRNA abundance rather than endogenous neuronal-cell-body protein localization; it does not resolve that specific assay-access limit. Supporting Evidence: GO_REF:0000033 file:human/CACNA1B/CACNA1B-uniprot.txt |
| GO:0045202 synapse | IEA GO_REF:0000108 | ACCEPT | Summary: CaV2.2 is a synaptic membrane channel. Reason: The inter-ontology inference from chemical synaptic transmission is consistent with independent presynaptic calcium influx and toxin-sensitive synaptic physiology. This is retained as the existing broad synapse location, without manufacturing a finer active-zone localization from interaction with a scaffold alone. |
| GO:0050804 modulation of chemical synaptic transmission | IDA PMID:23376566 Synthetic AΞ² oligomers (AΞ²(1-42) globulomer) modulate presyn... | ACCEPT | Summary: Changes in N-type channel activity modulate chemical synaptic transmission. Reason: PMID:23376566 reports prevention of amyloid-globulomer-induced synaptic deficits by specific N-type channel blockade. The channel directly controls calcium entry that regulates release, so the broad modulation process is part of its core function. The synthetic oligomer/slice-culture context is distinguished from an established physiological amyloid ligand mechanism. |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | MODIFY | Summary: The transmembrane-transport inference can be refined to the established calcium-import process. Reason: Target alpha1B pore function resolves both the transported ion and membrane direction more specifically than the InterPro-derived transmembrane-transport term. GO:0098703 matches calcium entry across plasma membrane and is already present in the target annotation set; this is a refinement, not a new independent process. Proposed replacements: calcium ion import across plasma membrane |
| GO:0070588 calcium ion transmembrane transport | IEA GO_REF:0000002 | ACCEPT | Summary: Alpha1B directly mediates calcium movement through the membrane. Reason: The InterPro-derived calcium-transport term is consistent with direct human channel electrophysiology and the calcium-selective pore. Calcium movement is the work performed by the channel itself, rather than a phenotype inferred solely from loss of an auxiliary protein. |
| GO:0098703 calcium ion import across plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: High-voltage opening permits extracellular calcium to enter the cytosol. Reason: The conserved PTN001295293 assertion is independently corroborated by the human alpha1B pore and whole-cell currents. The short list including a fungal source does not by itself invalidate a PAINT ancestral-node inference; the actual node placement was not independently reconstructed. The channel performs the calcium-import step directly. |
| GO:1903235 positive regulation of calcium ion-dependent exocytosis of neurotransmitter | ISS GO_REF:0000024 | ACCEPT | Summary: Presynaptic CaV2.2 calcium entry positively regulates neurotransmitter exocytosis. Reason: The exact ISS source Q02294 is the reviewed rat Cacna1b ortholog, whose indexed official record describes regulation of neurotransmitter release probability. The target human channel supplies calcium entry that triggers exocytosis, with independent channel and synaptic evidence supporting the conserved assertion. The original donor experiment was not independently re-read and this is not a claim that alpha1B catalyzes vesicle fusion. Supporting Evidence: GO_REF:0000024 file:human/CACNA1B/CACNA1B-uniprot.txt |
| GO:1904645 response to amyloid-beta | IDA PMID:23376566 Synthetic AΞ² oligomers (AΞ²(1-42) globulomer) modulate presyn... | KEEP AS NON CORE | Summary: Synthetic amyloid-beta oligomers alter N-type channel gating in the tested context. Reason: The complete PMID:23376566 abstract reports a hyperpolarizing shift of recombinant N-type channel activation after globulomer application and no effect of nonaggregated peptide. Retain the experimentally supported response as non-core contextual biology. It does not establish a normal endogenous amyloid receptor function or independently prove physical binding. Supporting Evidence: PMID:23376566 Application of non-aggregated AΞ² peptides had no effect |
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Download this section (compressed HTML)Q: Does amyloid-beta bind alpha1B directly under defined conditions, or is the observed current modulation mediated through another membrane or cellular component?
Q: How do the Alpha-1B-1 and Alpha-1B-2 products differ in native trafficking, gating and partner dependence, separately from disease-associated missense variants and other splice events?
Q: Which neuronal contexts support the curated CACNA1BβRXRB interaction, and which channel region was tested in the original fragment-based screen?
Experiment: Test physical amyloid-beta interaction with defined human CaV2.2 preparations alongside matched electrophysiology, using aggregation-state controls and independent binding readouts to distinguish contact from functional modulation.
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