CACNA1C encodes the pore-forming alpha1C subunit of CaV1.2, an L-type high-voltage-activated calcium channel. Its voltage sensors and calcium-selective pore convert plasma-membrane depolarization into calcium entry. In cardiac muscle this current contributes to the action potential and triggers ryanodine-receptor-mediated calcium release for contraction; in smooth muscle and neurons it links electrical activity to calcium-dependent responses. Beta and alpha2delta subunits regulate channel expression and gating, while calmodulin and other intracellular partners control inactivation and local signaling. Extensive alternative splicing changes gating, surface expression and pharmacology. Pathogenic variants can alter current density, selectivity or inactivation in different directions, producing cardiac and neurodevelopmental phenotypes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002520 immune system development | IMP PMID:15454078 Ca(V)1.2 calcium channel dysfunction causes a multisystem di... | UNDECIDED | Summary: Timothy syndrome includes immune abnormalities, but the specific immune-development assertion remains unresolved. Reason: The complete PMID:15454078 abstract reports immune deficiency. Selected primary clinical/developmental text additionally describes recurrent infections, but the inspected material does not resolve the specific immune-system ontogeny process defined by GO:0002520. The full immune-development evidence and supplementary clinical material were not inspected. Preserve the experimental assertion without treating a clinical immune phenotype as either proof of a particular developmental step or evidence that the annotation is false. Supporting Evidence: |
| GO:0005216 monoatomic ion channel activity | IEA GO_REF:0000002 | MODIFY | Summary: The channel-domain inference can be refined to the established high-voltage calcium-channel activity. Reason: InterPro correctly identifies an ion channel, while direct human channel expression and electrophysiology resolve the ion and voltage dependence. GO:0008331 includes L-type channels and is already present in the source set; this refines the same pore function without adding another core. Proposed replacements: high voltage-gated calcium channel activity |
| GO:0005245 voltage-gated calcium channel activity | IDA PMID:12130699 Effects of methylmercury on human neuronal L-type calcium ch... | ACCEPT | Summary: Recombinant human neuronal alpha1C supports voltage-gated calcium-channel activity. Reason: The complete PMID:12130699 abstract describes human neuronal alpha1C-1 coexpressed with alpha2b and beta3a in HEK293 cells. Whole-cell barium currents and their methylmercury sensitivity establish the functional calcium-channel preparation; barium used as the recording charge carrier is not a claim of physiological barium transport. Supporting Evidence: |
| GO:0005245 voltage-gated calcium channel activity | IDA PMID:16299511 Insights into voltage-gated calcium channel regulation from ... | ACCEPT | Summary: Human CaV1.2 gating and its calmodulin-dependent regulation support the channel activity. Reason: The complete abstract and selected Methods/Results of PMID:16299511 describe human CaV1.2 IQ-domain/calmodulin structure and channel recordings with auxiliary subunits in Xenopus oocytes. Channel activity belongs to alpha1C, while calmodulin binding modulates inactivation and facilitation. Supporting Evidence: |
| GO:0005245 voltage-gated calcium channel activity | IDA PMID:28119464 Ser1928 phosphorylation by PKA stimulates the L-type Ca2+ ch... | ACCEPT | Summary: Arterial CaV1.2 currents support the calcium-channel function. Reason: PMID:28119464 includes native arterial myocyte recordings and human arterial observations alongside mouse genetic experiments. The inspected human Results support glucose-associated enhancement of channel activity in the stated PKA/Ser1928 context. Phosphorylation regulates the channel; kinase activity is not assigned to alpha1C. Supporting Evidence: |
| GO:0005245 voltage-gated calcium channel activity | IDA PMID:29078335 Structural insights into binding of STAC proteins to voltage... | ACCEPT | Summary: STAC-dependent modulation was tested on functional CaV1.2 channels. Reason: PMID:29078335 includes human CaV1.2 alpha1C-77 with auxiliary subunits in Xenopus oocytes and calcium/barium current measurements. Its CaV1.1 structural emphasis does not make the CaV1.2 annotation a paralog error. STAC-mediated suppression of calcium-dependent inactivation regulates the target pore. Supporting Evidence: |
| GO:0005245 voltage-gated calcium channel activity | IDA PMID:8392192 Cloning, chromosomal localization, and functional expression... | ACCEPT | Summary: Cloned human cardiac alpha1C forms a functional voltage-dependent channel. Reason: The complete PMID:8392192 abstract reports expression of cloned human cardiac alpha1C in Xenopus oocytes and characteristic L-type channel properties. Full individual traces and every auxiliary-subunit condition were not independently inspected. Supporting Evidence: PMID:8392192 single-channel analyses revealed native-like pharmacology and channel properties |
| GO:0005245 voltage-gated calcium channel activity | IEA GO_REF:0000002 | ACCEPT | Summary: The calcium-channel domain inference agrees with direct target experiments. Reason: The InterPro-derived assignment is independently supported by cloned human alpha1C currents and pore mutagenesis. It does not depend on assuming that every protein with a channel-associated domain forms a pore. |
| GO:0005245 voltage-gated calcium channel activity | IMP PMID:15863612 Severe arrhythmia disorder caused by cardiac L-type calcium ... | ACCEPT | Summary: WT and Timothy-syndrome channel comparisons establish calcium-channel function. Reason: The complete PMID:15863612 abstract reports heterologous WT/mutant channels and marked loss of inactivation for G406R/G402S. Cardiomyocyte action-potential consequences include computational modeling; those are distinguished from direct recordings of the expressed channels. Supporting Evidence: |
| GO:0005245 voltage-gated calcium channel activity | IMP PMID:20953164 Multiple C-terminal tail Ca(2+)/CaMs regulate Ca(V)1.2 funct... | ACCEPT | Summary: Calmodulin-tail interactions regulate an experimentally functional CaV1.2 pore. Reason: PMID:20953164 combines tail/calmodulin structures and electrophysiology. Its proposed multiple calmodulin contacts do not establish physiological channel dimerization, which the paper itself rejects. The indexed official correction concerns an affiliation and does not replace the functional results. Supporting Evidence: |
| GO:0005245 voltage-gated calcium channel activity | IMP PMID:24728418 Long QT syndrome type 8: novel CACNA1C mutations causing QT ... | ACCEPT | Summary: Functional analysis of long-QT-associated variants supports calcium-channel activity. Reason: The complete PMID:24728418 abstract reports whole-cell recordings of WT and patient-associated channels, including increased peak current for R858H and slower inactivation for A582D. Different variants are not collapsed into one universal gain-of-function mechanism. Supporting Evidence: |
| GO:0005245 voltage-gated calcium channel activity | IMP PMID:25260352 Novel Timothy syndrome mutation leading to increase in CACNA... | ACCEPT | Summary: I1166T changes CaV1.2 gating while preserving its identity as a calcium channel. Reason: The complete PMID:25260352 abstract describes decreased peak current density together with an increased window current and altered inactivation. Both loss- and gain-related features are retained rather than treating the disease variant as a simple measure of normal channel activation. Supporting Evidence: |
| GO:0005245 voltage-gated calcium channel activity | IMP PMID:27218670 Molecular and Functional Characterization of Rare CACNA1C Va... | ACCEPT | Summary: WT and rare variant recordings substantiate calcium-channel function. Reason: The complete PMID:27218670 abstract describes HEK293 patch-clamp characterization of CACNA1C variants found in a sudden-death cohort. Functional measurements support the pore activity independently of whether every rare variant is causally responsible for disease. Supporting Evidence: |
| GO:0005245 voltage-gated calcium channel activity | IMP PMID:31430211 Characterization of the CACNA1C-R518C Missense Mutation in t... | ACCEPT | Summary: Human induced-pluripotent-stem-cell cardiomyocytes support target channel activity. Reason: The complete PMID:31430211 abstract describes R518C patient-derived and isogenic cardiomyocytes, action-potential prolongation and L-type current perturbation. This provides a human cardiomyocyte context distinct from the earlier heterologous R518 assays; full traces and supplementary data were not inspected. Supporting Evidence: |
| GO:0005245 voltage-gated calcium channel activity | IMP PMID:8099908 Molecular localization of ion selectivity sites within the p... | ACCEPT | Summary: Human alpha1C pore mutagenesis directly tests calcium-channel selectivity. Reason: The complete PMID:8099908 abstract describes ion-selectivity mutations in a human cardiac L-type channel. Changes produced by engineered pore residues inform the WT calcium-selective channel and are not generalized into a WT nonselective conductance. Supporting Evidence: PMID:8099908 replacing Glu residues at this position alters the ion selectivity |
| GO:0005515 protein binding | IPI PMID:11438518 Direct interaction of the Rab3 effector RIM with Ca2+ channe... | KEEP AS NON CORE | Summary: RIM association includes weaker binding to the alpha1C channel. Reason: PMID:11438518 explicitly reports interaction of RIM C2 domains with alpha1C, although the stronger quantified interaction is with alpha1B. Retain the curated Q86UR5 association as non-core; the abstract does not establish a native human CACNA1C release-site mechanism or transfer RIM scaffold activity to the channel. Full construct-level Methods were not inspected. Supporting Evidence: PMID:11438518 They also weakly interact with the alpha1C |
| GO:0005515 protein binding | IPI PMID:15140941 Ca2+-binding protein-1 facilitates and forms a postsynaptic ... | KEEP AS NON CORE | Summary: CABP1 binds the CACNA1C C-terminal regulatory region. Reason: PMID:15140941 reports CABP1 binding to channel fragments and association with the channel; UniProt independently records this exact CABP1 edge. The study uses human short CABP1, rbcII channel constructs, HEK293T assays and rat native postsynaptic fractions. Retain this regulatory association as non-core without assigning CABP1 sensor activity to CACNA1C or calling CABP1 calmodulin. |
| GO:0005515 protein binding | IPI PMID:18535142 Calmodulin-dependent gating of Ca(v)1.2 calcium channels in ... | KEEP AS NON CORE | Summary: Association with the auxiliary beta subunit CACNB3/P54284. Reason: PMID:18535142 investigates human vascular alpha1C with beta2d and calmodulin in COS1 cells, including conditions lacking beta subunits. That experimental absence is not a negation of the established channel-beta interaction. Retain the exact curated CACNB3/P54284 edge, independently present in UniProt, as non-core. The specific original positive assay for this exact accession/isoform was not separately resolved; neither endogenous-beta negative controls nor the beta2d construct establish all three partner-specific assays. |
| GO:0005515 protein binding | IPI PMID:18535142 Calmodulin-dependent gating of Ca(v)1.2 calcium channels in ... | KEEP AS NON CORE | Summary: Association with the auxiliary beta subunit CACNB1/Q02641-1. Reason: PMID:18535142 investigates human vascular alpha1C with beta2d and calmodulin in COS1 cells, including conditions lacking beta subunits. That experimental absence is not a negation of the established channel-beta interaction. Retain the exact curated CACNB1/Q02641-1 edge, independently present in UniProt, as non-core. The specific original positive assay for this exact accession/isoform was not separately resolved; neither endogenous-beta negative controls nor the beta2d construct establish all three partner-specific assays. |
| GO:0005515 protein binding | IPI PMID:18535142 Calmodulin-dependent gating of Ca(v)1.2 calcium channels in ... | KEEP AS NON CORE | Summary: Association with the auxiliary beta subunit CACNB2/Q08289-1. Reason: PMID:18535142 investigates human vascular alpha1C with beta2d and calmodulin in COS1 cells, including conditions lacking beta subunits. That experimental absence is not a negation of the established channel-beta interaction. Retain the exact curated CACNB2/Q08289-1 edge, independently present in UniProt, as non-core. The specific original positive assay for this exact accession/isoform was not separately resolved; neither endogenous-beta negative controls nor the beta2d construct establish all three partner-specific assays. |
| GO:0005515 protein binding | IPI PMID:21653829 Protein interactome reveals converging molecular pathways am... | MODIFY | Summary: The curated ACTN1 interaction supports alpha-actinin binding. Reason: PMID:21653829 provides a stringent, retested binary Y2H interaction framework, and UniProt records the exact CACNA1CβP12814/ACTN1 edge. GO:0051393 covers binding to alpha-actinin and is more informative than protein binding for this known partner. The individual supplementary target cell and its orthogonal validation were not inspected; this refinement retains curator-supported partner identity without claiming the separate ACTN2 cardiac mechanism for ACTN1. Proposed replacements: alpha-actinin binding |
| GO:0005515 protein binding | IPI PMID:21653829 Protein interactome reveals converging molecular pathways am... | KEEP AS NON CORE | Summary: PICK1 is a curated interaction partner of CACNA1C. Reason: PMID:21653829 describes a human-cDNA Y2H screen with independent retesting, and the exact Q9NRD5/PICK1 interaction is recorded by UniProt. Retain the source-specific association as non-core. The original target table and a CACNA1C-specific PICK1-domain assay were not inspected, so no finer PDZ-binding or trafficking activity is inferred. |
| GO:0005515 protein binding | IPI PMID:37207277 Using brain cell-type-specific protein interactomes to inter... | KEEP AS NON CORE | Summary: SF3B1 is a curated CACNA1C-associated protein in a human neuronal interactome. Reason: PMID:37207277 profiles endogenous CACNA1C by replicate IP-MS in human induced excitatory neurons; the exact O75533/SF3B1 edge is independently recorded in UniProt. Retain the association as non-core. The paper deliberately includes co-complex and transient associations, so this does not establish a purified direct interface or confer the partnerβs activity on CACNA1C. Individual supplementary target statistics and pair-specific reverse-IP validation were not inspected. |
| GO:0005515 protein binding | IPI PMID:37207277 Using brain cell-type-specific protein interactomes to inter... | KEEP AS NON CORE | Summary: C3 is a curated CACNA1C-associated protein in a human neuronal interactome. Reason: PMID:37207277 profiles endogenous CACNA1C by replicate IP-MS in human induced excitatory neurons; the exact P01024/C3 edge is independently recorded in UniProt. Retain the association as non-core. The paper deliberately includes co-complex and transient associations, so this does not establish a purified direct interface or confer the partnerβs activity on CACNA1C. Individual supplementary target statistics and pair-specific reverse-IP validation were not inspected. The article also explicitly identifies C3 in one CACNA1C IP; it does not establish a complement-receptor mechanism. |
| GO:0005515 protein binding | IPI PMID:37207277 Using brain cell-type-specific protein interactomes to inter... | KEEP AS NON CORE | Summary: HNRNPA2B1 is a curated CACNA1C-associated protein in a human neuronal interactome. Reason: PMID:37207277 profiles endogenous CACNA1C by replicate IP-MS in human induced excitatory neurons; the exact P22626/HNRNPA2B1 edge is independently recorded in UniProt. Retain the association as non-core. The paper deliberately includes co-complex and transient associations, so this does not establish a purified direct interface or confer the partnerβs activity on CACNA1C. Individual supplementary target statistics and pair-specific reverse-IP validation were not inspected. |
| GO:0005515 protein binding | IPI PMID:37207277 Using brain cell-type-specific protein interactomes to inter... | KEEP AS NON CORE | Summary: NSG1 is a curated CACNA1C-associated protein in a human neuronal interactome. Reason: PMID:37207277 profiles endogenous CACNA1C by replicate IP-MS in human induced excitatory neurons; the exact P42857/NSG1 edge is independently recorded in UniProt. Retain the association as non-core. The paper deliberately includes co-complex and transient associations, so this does not establish a purified direct interface or confer the partnerβs activity on CACNA1C. Individual supplementary target statistics and pair-specific reverse-IP validation were not inspected. |
| GO:0005515 protein binding | IPI PMID:37207277 Using brain cell-type-specific protein interactomes to inter... | KEEP AS NON CORE | Summary: FXR1 is a curated CACNA1C-associated protein in a human neuronal interactome. Reason: PMID:37207277 profiles endogenous CACNA1C by replicate IP-MS in human induced excitatory neurons; the exact P51114/FXR1 edge is independently recorded in UniProt. Retain the association as non-core. The paper deliberately includes co-complex and transient associations, so this does not establish a purified direct interface or confer the partnerβs activity on CACNA1C. Individual supplementary target statistics and pair-specific reverse-IP validation were not inspected. |
| GO:0005515 protein binding | IPI PMID:37207277 Using brain cell-type-specific protein interactomes to inter... | KEEP AS NON CORE | Summary: CACNB3 is a curated CACNA1C-associated protein in a human neuronal interactome. Reason: PMID:37207277 profiles endogenous CACNA1C by replicate IP-MS in human induced excitatory neurons; the exact P54284/CACNB3 edge is independently recorded in UniProt. Retain the association as non-core. The paper deliberately includes co-complex and transient associations, so this does not establish a purified direct interface or confer the partnerβs activity on CACNA1C. Individual supplementary target statistics and pair-specific reverse-IP validation were not inspected. The Results additionally recover known beta-channel components, including CACNB3. |
| GO:0005515 protein binding | IPI PMID:37207277 Using brain cell-type-specific protein interactomes to inter... | KEEP AS NON CORE | Summary: MEF2C is a curated CACNA1C-associated protein in a human neuronal interactome. Reason: PMID:37207277 profiles endogenous CACNA1C by replicate IP-MS in human induced excitatory neurons; the exact Q06413/MEF2C edge is independently recorded in UniProt. Retain the association as non-core. The paper deliberately includes co-complex and transient associations, so this does not establish a purified direct interface or confer the partnerβs activity on CACNA1C. Individual supplementary target statistics and pair-specific reverse-IP validation were not inspected. |
| GO:0005515 protein binding | IPI PMID:37207277 Using brain cell-type-specific protein interactomes to inter... | KEEP AS NON CORE | Summary: APLP2 is a curated CACNA1C-associated protein in a human neuronal interactome. Reason: PMID:37207277 profiles endogenous CACNA1C by replicate IP-MS in human induced excitatory neurons; the exact Q06481/APLP2 edge is independently recorded in UniProt. Retain the association as non-core. The paper deliberately includes co-complex and transient associations, so this does not establish a purified direct interface or confer the partnerβs activity on CACNA1C. Individual supplementary target statistics and pair-specific reverse-IP validation were not inspected. |
| GO:0005515 protein binding | IPI PMID:37207277 Using brain cell-type-specific protein interactomes to inter... | KEEP AS NON CORE | Summary: PDE4B is a curated CACNA1C-associated protein in a human neuronal interactome. Reason: PMID:37207277 profiles endogenous CACNA1C by replicate IP-MS in human induced excitatory neurons; the exact Q07343/PDE4B edge is independently recorded in UniProt. Retain the association as non-core. The paper deliberately includes co-complex and transient associations, so this does not establish a purified direct interface or confer the partnerβs activity on CACNA1C. Individual supplementary target statistics and pair-specific reverse-IP validation were not inspected. |
| GO:0005515 protein binding | IPI PMID:37207277 Using brain cell-type-specific protein interactomes to inter... | KEEP AS NON CORE | Summary: MSI2 is a curated CACNA1C-associated protein in a human neuronal interactome. Reason: PMID:37207277 profiles endogenous CACNA1C by replicate IP-MS in human induced excitatory neurons; the exact Q96DH6/MSI2 edge is independently recorded in UniProt. Retain the association as non-core. The paper deliberately includes co-complex and transient associations, so this does not establish a purified direct interface or confer the partnerβs activity on CACNA1C. Individual supplementary target statistics and pair-specific reverse-IP validation were not inspected. |
| GO:0005515 protein binding | IPI PMID:37207277 Using brain cell-type-specific protein interactomes to inter... | KEEP AS NON CORE | Summary: SEMA4C is a curated CACNA1C-associated protein in a human neuronal interactome. Reason: PMID:37207277 profiles endogenous CACNA1C by replicate IP-MS in human induced excitatory neurons; the exact Q9C0C4/SEMA4C edge is independently recorded in UniProt. Retain the association as non-core. The paper deliberately includes co-complex and transient associations, so this does not establish a purified direct interface or confer the partnerβs activity on CACNA1C. Individual supplementary target statistics and pair-specific reverse-IP validation were not inspected. |
| GO:0005515 protein binding | IPI PMID:37207277 Using brain cell-type-specific protein interactomes to inter... | KEEP AS NON CORE | Summary: KIAA1549 is a curated CACNA1C-associated protein in a human neuronal interactome. Reason: PMID:37207277 profiles endogenous CACNA1C by replicate IP-MS in human induced excitatory neurons; the exact Q9HCM3/KIAA1549 edge is independently recorded in UniProt. Retain the association as non-core. The paper deliberately includes co-complex and transient associations, so this does not establish a purified direct interface or confer the partnerβs activity on CACNA1C. Individual supplementary target statistics and pair-specific reverse-IP validation were not inspected. |
| GO:0005515 protein binding | IPI PMID:37207277 Using brain cell-type-specific protein interactomes to inter... | KEEP AS NON CORE | Summary: PICK1 is a curated CACNA1C-associated protein in a human neuronal interactome. Reason: PMID:37207277 profiles endogenous CACNA1C by replicate IP-MS in human induced excitatory neurons; the exact Q9NRD5/PICK1 edge is independently recorded in UniProt. Retain the association as non-core. The paper deliberately includes co-complex and transient associations, so this does not establish a purified direct interface or confer the partnerβs activity on CACNA1C. Individual supplementary target statistics and pair-specific reverse-IP validation were not inspected. |
| GO:0005515 protein binding | IPI PMID:37207277 Using brain cell-type-specific protein interactomes to inter... | KEEP AS NON CORE | Summary: RALY is a curated CACNA1C-associated protein in a human neuronal interactome. Reason: PMID:37207277 profiles endogenous CACNA1C by replicate IP-MS in human induced excitatory neurons; the exact Q9UKM9/RALY edge is independently recorded in UniProt. Retain the association as non-core. The paper deliberately includes co-complex and transient associations, so this does not establish a purified direct interface or confer the partnerβs activity on CACNA1C. Individual supplementary target statistics and pair-specific reverse-IP validation were not inspected. |
| GO:0005515 protein binding | IPI PMID:37207277 Using brain cell-type-specific protein interactomes to inter... | KEEP AS NON CORE | Summary: PCDHB5 is a curated CACNA1C-associated protein in a human neuronal interactome. Reason: PMID:37207277 profiles endogenous CACNA1C by replicate IP-MS in human induced excitatory neurons; the exact Q9Y5E4/PCDHB5 edge is independently recorded in UniProt. Retain the association as non-core. The paper deliberately includes co-complex and transient associations, so this does not establish a purified direct interface or confer the partnerβs activity on CACNA1C. Individual supplementary target statistics and pair-specific reverse-IP validation were not inspected. |
| GO:0005515 protein binding | IPI PMID:37207277 Using brain cell-type-specific protein interactomes to inter... | KEEP AS NON CORE | Summary: PCDHA2 is a curated CACNA1C-associated protein in a human neuronal interactome. Reason: PMID:37207277 profiles endogenous CACNA1C by replicate IP-MS in human induced excitatory neurons; the exact Q9Y5H9/PCDHA2 edge is independently recorded in UniProt. Retain the association as non-core. The paper deliberately includes co-complex and transient associations, so this does not establish a purified direct interface or confer the partnerβs activity on CACNA1C. Individual supplementary target statistics and pair-specific reverse-IP validation were not inspected. |
| GO:0005516 calmodulin binding | IPI PMID:15140941 Ca2+-binding protein-1 facilitates and forms a postsynaptic ... | ACCEPT | Summary: Calmodulin binding supplies intrinsic calcium-dependent channel feedback. Reason: PMID:15140941 directly compares purified calmodulin and CABP1 binding to channel C-terminal fragments; the C and IQ sites bind calmodulin. This is a mechanistic interaction in calcium-dependent channel gating and can be subsumed within the channel core. Preserve the exact CALM accession in this source row; the purified calmodulin reagent does not separately resolve CALM1, CALM2 and CALM3 gene-specific experiments. Supporting Evidence: PMID:15140941 IQ domain, is Ca2+ dependent and competitive with CaM binding |
| GO:0005516 calmodulin binding | IPI PMID:15140941 Ca2+-binding protein-1 facilitates and forms a postsynaptic ... | ACCEPT | Summary: Calmodulin binding supplies intrinsic calcium-dependent channel feedback. Reason: PMID:15140941 directly compares purified calmodulin and CABP1 binding to channel C-terminal fragments; the C and IQ sites bind calmodulin. This is a mechanistic interaction in calcium-dependent channel gating and can be subsumed within the channel core. Preserve the exact CALM accession in this source row; the purified calmodulin reagent does not separately resolve CALM1, CALM2 and CALM3 gene-specific experiments. Supporting Evidence: |
| GO:0005516 calmodulin binding | IPI PMID:15140941 Ca2+-binding protein-1 facilitates and forms a postsynaptic ... | ACCEPT | Summary: Calmodulin binding supplies intrinsic calcium-dependent channel feedback. Reason: PMID:15140941 directly compares purified calmodulin and CABP1 binding to channel C-terminal fragments; the C and IQ sites bind calmodulin. This is a mechanistic interaction in calcium-dependent channel gating and can be subsumed within the channel core. Preserve the exact CALM accession in this source row; the purified calmodulin reagent does not separately resolve CALM1, CALM2 and CALM3 gene-specific experiments. Supporting Evidence: |
| GO:0005737 cytoplasm | IDA PMID:11206130 Triad proteins and intracellular Ca2+ transients during deve... | KEEP AS NON CORE | Summary: An intracellular alpha1C pool is retained alongside its principal plasma-membrane location. Reason: PMID:11206130 examines developing human skeletal muscle cultures. Its complete abstract emphasizes alpha1C at the plasma membrane and alpha1S in the cytoplasm; the original target-specific cytoplasm observation was not independently resolved from the full paper. Retain the broad curated alpha1C location with independent evidence for intracellular CaV1.2 trafficking pools in PMID:34072954, without transferring the alpha1S result or asserting soluble cytosolic channel protein. Supporting Evidence: PMID:34072954 internal reservoirs of preformed CaV1.2 channels file:human/CACNA1C/CACNA1C-uniprot.txt |
| GO:0005737 cytoplasm | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: The broad cytoplasmic location includes intracellular channel trafficking pools. Reason: The ARBA inference is compatible with intracellular membrane-associated CaV1.2 pools described in the complete PMID:34072954 review abstract. Cytoplasm is not equated with cytosol, and the principal functional channel location remains plasma membrane. |
| GO:0005886 plasma membrane | EXP PMID:11741969 A novel long N-terminal isoform of human L-type Ca2+ channel... | ACCEPT | Summary: The experimental channel preparation supports plasma-membrane localization. Reason: The inspected source supports human long-N-terminal channels expressed in Xenopus oocytes, with isoform-dependent PKC regulation. Functional transmembrane currents and, where explicitly reported, surface measurements support the existing location. This does not establish identical abundance in every native tissue or all 37 named products. Supporting Evidence: |
| GO:0005886 plasma membrane | EXP PMID:12176756 alpha(1C) (Ca(V)1.2) L-type calcium channel mediates mechano... | ACCEPT | Summary: The experimental channel preparation supports plasma-membrane localization. Reason: The inspected source supports cloned human intestinal alpha1C expressed in HEK/CHO cells for mechanosensitive current measurements. Functional transmembrane currents and, where explicitly reported, surface measurements support the existing location. This does not establish identical abundance in every native tissue or all 37 named products. Supporting Evidence: |
| GO:0005886 plasma membrane | EXP PMID:12181424 Molecular cloning and characterization of the human voltage-... | ACCEPT | Summary: The experimental channel preparation supports plasma-membrane localization. Reason: The inspected source supports human alpha2delta4 coexpression with CaV1.2 and beta3 in HEK293 cells, supporting a functional target channel despite the auxiliary-subunit focus. Functional transmembrane currents and, where explicitly reported, surface measurements support the existing location. This does not establish identical abundance in every native tissue or all 37 named products. Supporting Evidence: |
| GO:0005886 plasma membrane | EXP PMID:15454078 Ca(V)1.2 calcium channel dysfunction causes a multisystem di... | ACCEPT | Summary: The experimental channel preparation supports plasma-membrane localization. Reason: The inspected source supports WT and G406R alpha1C currents in heterologous cells. Functional transmembrane currents and, where explicitly reported, surface measurements support the existing location. This does not establish identical abundance in every native tissue or all 37 named products. Supporting Evidence: |
| GO:0005886 plasma membrane | EXP PMID:15863612 Severe arrhythmia disorder caused by cardiac L-type calcium ... | ACCEPT | Summary: The experimental channel preparation supports plasma-membrane localization. Reason: The inspected source supports human WT and Timothy-syndrome mutant channel currents. Functional transmembrane currents and, where explicitly reported, surface measurements support the existing location. This does not establish identical abundance in every native tissue or all 37 named products. Supporting Evidence: |
| GO:0005886 plasma membrane | EXP PMID:16299511 Insights into voltage-gated calcium channel regulation from ... | ACCEPT | Summary: The experimental channel preparation supports plasma-membrane localization. Reason: The inspected source supports human alpha1C-77 with auxiliary subunits in Xenopus oocytes. Functional transmembrane currents and, where explicitly reported, surface measurements support the existing location. This does not establish identical abundance in every native tissue or all 37 named products. Supporting Evidence: |
| GO:0005886 plasma membrane | EXP PMID:17071743 Atherosclerosis-related molecular alteration of the human Ca... | ACCEPT | Summary: The experimental channel preparation supports plasma-membrane localization. Reason: The inspected source supports human vascular alpha1C splice changes and expression assays. Functional transmembrane currents and, where explicitly reported, surface measurements support the existing location. This does not establish identical abundance in every native tissue or all 37 named products. Supporting Evidence: |
| GO:0005886 plasma membrane | EXP PMID:17224476 Loss-of-function mutations in the cardiac calcium channel un... | ACCEPT | Summary: The experimental channel preparation supports plasma-membrane localization. Reason: The inspected source supports human WT/mutant alpha1C in CHO-K1 cells, including a trafficking defect for A39V but not G490R. Functional transmembrane currents and, where explicitly reported, surface measurements support the existing location. This does not establish identical abundance in every native tissue or all 37 named products. Supporting Evidence: |
| GO:0005886 plasma membrane | EXP PMID:20953164 Multiple C-terminal tail Ca(2+)/CaMs regulate Ca(V)1.2 funct... | ACCEPT | Summary: The experimental channel preparation supports plasma-membrane localization. Reason: The inspected source supports functional full-length channel assays accompanying calmodulin-tail studies. Functional transmembrane currents and, where explicitly reported, surface measurements support the existing location. This does not establish identical abundance in every native tissue or all 37 named products. Supporting Evidence: |
| GO:0005886 plasma membrane | EXP PMID:24728418 Long QT syndrome type 8: novel CACNA1C mutations causing QT ... | ACCEPT | Summary: The experimental channel preparation supports plasma-membrane localization. Reason: The inspected source supports WT and long-QT-associated channel patch-clamp recordings. Functional transmembrane currents and, where explicitly reported, surface measurements support the existing location. This does not establish identical abundance in every native tissue or all 37 named products. Supporting Evidence: |
| GO:0005886 plasma membrane | EXP PMID:26253506 Identification and Functional Characterization of a Novel CA... | ACCEPT | Summary: The experimental channel preparation supports plasma-membrane localization. Reason: The inspected source supports human EYFP-alpha1C-77 in HEK293 cells, with confocal surface-to-central fluorescence and currents. Functional transmembrane currents and, where explicitly reported, surface measurements support the existing location. This does not establish identical abundance in every native tissue or all 37 named products. Supporting Evidence: PMID:26253506 loss of current density and inactivation in combination with increased window and late current |
| GO:0005886 plasma membrane | EXP PMID:27218670 Molecular and Functional Characterization of Rare CACNA1C Va... | ACCEPT | Summary: The experimental channel preparation supports plasma-membrane localization. Reason: The inspected source supports WT and rare human variant channels tested by HEK293 patch clamp. Functional transmembrane currents and, where explicitly reported, surface measurements support the existing location. This does not establish identical abundance in every native tissue or all 37 named products. Supporting Evidence: |
| GO:0005886 plasma membrane | EXP PMID:29078335 Structural insights into binding of STAC proteins to voltage... | ACCEPT | Summary: The experimental channel preparation supports plasma-membrane localization. Reason: The inspected source supports human alpha1C-77 with STAC and auxiliary subunits in Xenopus oocytes. Functional transmembrane currents and, where explicitly reported, surface measurements support the existing location. This does not establish identical abundance in every native tissue or all 37 named products. Supporting Evidence: |
| GO:0005886 plasma membrane | EXP PMID:29742403 Alternative Splicing at N Terminus and Domain I Modulates Ca... | ACCEPT | Summary: The experimental channel preparation supports plasma-membrane localization. Reason: The inspected source supports human channel splice constructs in HEK cells, including surface biotinylation. Functional transmembrane currents and, where explicitly reported, surface measurements support the existing location. This does not establish identical abundance in every native tissue or all 37 named products. The official 2018 correction replaces duplicated exemplary traces in Figure 7; corrected images were not inspected, and no claim is made that the surface-biotinylation experiment was replaced. Supporting Evidence: |
| GO:0005886 plasma membrane | EXP PMID:7737988 Different voltage-dependent inhibition by dihydropyridines o... | ACCEPT | Summary: The experimental channel preparation supports plasma-membrane localization. Reason: The inspected source supports human channel splice variants expressed in Xenopus oocytes. Functional transmembrane currents and, where explicitly reported, surface measurements support the existing location. This does not establish identical abundance in every native tissue or all 37 named products. Supporting Evidence: |
| GO:0005886 plasma membrane | EXP PMID:8099908 Molecular localization of ion selectivity sites within the p... | ACCEPT | Summary: The experimental channel preparation supports plasma-membrane localization. Reason: The inspected source supports engineered human alpha1C pore mutants. Functional transmembrane currents and, where explicitly reported, surface measurements support the existing location. This does not establish identical abundance in every native tissue or all 37 named products. Supporting Evidence: |
| GO:0005886 plasma membrane | EXP PMID:8392192 Cloning, chromosomal localization, and functional expression... | ACCEPT | Summary: The experimental channel preparation supports plasma-membrane localization. Reason: The inspected source supports cloned human cardiac alpha1C expressed in Xenopus oocytes. Functional transmembrane currents and, where explicitly reported, surface measurements support the existing location. This does not establish identical abundance in every native tissue or all 37 named products. Supporting Evidence: |
| GO:0005886 plasma membrane | EXP PMID:9013606 Molecular structures involved in L-type calcium channel inac... | ACCEPT | Summary: The experimental channel preparation supports plasma-membrane localization. Reason: The inspected source supports human alpha1C C-terminal splice variants. Functional transmembrane currents and, where explicitly reported, surface measurements support the existing location. This does not establish identical abundance in every native tissue or all 37 named products. Supporting Evidence: |
| GO:0005886 plasma membrane | EXP PMID:9087614 Properties of three COOH-terminal splice variants of a human... | ACCEPT | Summary: The experimental channel preparation supports plasma-membrane localization. Reason: The inspected source supports human cardiac C-terminal variants in Xenopus/HEK expression systems. Functional transmembrane currents and, where explicitly reported, surface measurements support the existing location. This does not establish identical abundance in every native tissue or all 37 named products. Supporting Evidence: |
| GO:0005886 plasma membrane | EXP PMID:9607315 Ca2+ channel sensitivity towards the blocker isradipine is a... | ACCEPT | Summary: The experimental channel preparation supports plasma-membrane localization. Reason: The inspected source supports human alpha1C splice variants tested for isradipine sensitivity. Functional transmembrane currents and, where explicitly reported, surface measurements support the existing location. This does not establish identical abundance in every native tissue or all 37 named products. Supporting Evidence: |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: The curated immunofluorescence location agrees with direct target channel evidence. Reason: The original Human Protein Atlas images were not independently re-examined. Plasma-membrane localization is nevertheless independently established by human alpha1C surface measurements and electrophysiology, so retain the experimental curation with that corroboration. Supporting Evidence: GO_REF:0000052 file:human/CACNA1C/CACNA1C-uniprot.txt |
| GO:0005886 plasma membrane | IDA PMID:11206130 Triad proteins and intracellular Ca2+ transients during deve... | ACCEPT | Summary: Human developing muscle cultures place alpha1C at the plasma membrane. Reason: The complete PMID:11206130 abstract explicitly distinguishes alpha1C membrane expression from predominantly cytoplasmic alpha1S. Alpha1C expression decreases as the innervated cultures mature; no universal mature-skeletal-muscle predominance is inferred. Supporting Evidence: |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: The propagated plasma-membrane location is independently established for human alpha1C. Reason: The original mapping or ortholog-transfer provenance is preserved. Human recombinant currents and direct surface measurements corroborate plasma-membrane localization without requiring a new target experiment to revalidate every conserved source record. The precise donor experiment or mapping implementation was not independently reconstructed. Supporting Evidence: GO_REF:0000044 file:human/CACNA1C/CACNA1C-uniprot.txt |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: The propagated plasma-membrane location is independently established for human alpha1C. Reason: The original mapping or ortholog-transfer provenance is preserved. Human recombinant currents and direct surface measurements corroborate plasma-membrane localization without requiring a new target experiment to revalidate every conserved source record. The precise donor experiment or mapping implementation was not independently reconstructed. Supporting Evidence: GO_REF:0000024 file:human/CACNA1C/CACNA1C-uniprot.txt |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-265645 | ACCEPT | Summary: The LTCC event is consistent with alpha1C at the plasma membrane. Reason: The complete cached Reactome summary supplies calcium-entry or channel-pharmacology context; the compartment assertion is carried by the preserved Reactome-derived GOA record. Independent human channel evidence supports plasma membrane. The event text is not represented as a separate localization experiment or as proof of every auxiliary-subunit combination. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5577213 | ACCEPT | Summary: The LTCC event is consistent with alpha1C at the plasma membrane. Reason: The complete cached Reactome summary supplies calcium-entry or channel-pharmacology context; the compartment assertion is carried by the preserved Reactome-derived GOA record. Independent human channel evidence supports plasma membrane. The event text is not represented as a separate localization experiment or as proof of every auxiliary-subunit combination. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9614031 | ACCEPT | Summary: The LTCC event is consistent with alpha1C at the plasma membrane. Reason: The complete cached Reactome summary supplies calcium-entry or channel-pharmacology context; the compartment assertion is carried by the preserved Reactome-derived GOA record. Independent human channel evidence supports plasma membrane. The event text is not represented as a separate localization experiment or as proof of every auxiliary-subunit combination. |
| GO:0005891 voltage-gated calcium channel complex | IBA GO_REF:0000033 | ACCEPT | Summary: Alpha1C is the pore-forming component of a voltage-gated calcium-channel complex. Reason: The PTN001295293 PAINT assertion agrees with direct human channel reconstitution. The target in WITH/FROM is legitimate descendant experimental grounding, not circularity; exact node placement was not re-created. Auxiliary subunits regulate assembly and gating; their participation does not change alpha1C into an auxiliary regulator. |
| GO:0005891 voltage-gated calcium channel complex | IDA PMID:12130699 Effects of methylmercury on human neuronal L-type calcium ch... | ACCEPT | Summary: Alpha1C is the pore-forming component of a voltage-gated calcium-channel complex. Reason: PMID:12130699 coexpresses human neuronal alpha1C-1 with alpha2b and beta3a in HEK293 cells. Auxiliary subunits regulate assembly and gating; their participation does not change alpha1C into an auxiliary regulator. |
| GO:0005891 voltage-gated calcium channel complex | IDA PMID:17224476 Loss-of-function mutations in the cardiac calcium channel un... | ACCEPT | Summary: Alpha1C is the pore-forming component of a voltage-gated calcium-channel complex. Reason: PMID:17224476 coexpresses human alpha1C with beta2b and alpha2delta1 in CHO-K1 cells. Auxiliary subunits regulate assembly and gating; their participation does not change alpha1C into an auxiliary regulator. |
| GO:0005891 voltage-gated calcium channel complex | IEA GO_REF:0000002 | ACCEPT | Summary: Alpha1C is the pore-forming component of a voltage-gated calcium-channel complex. Reason: The InterPro inference is independently supported by human channel coexpression and functional assembly. Auxiliary subunits regulate assembly and gating; their participation does not change alpha1C into an auxiliary regulator. |
| GO:0006811 monoatomic ion transport | IEA GO_REF:0000002 | MODIFY | Summary: The broad transport inference can be refined to calcium import across plasma membrane. Reason: Human alpha1C directly conducts inward calcium current. The verified GO:0098703 definition specifies calcium movement from outside the cell into the cytosol across plasma membrane, matching the target mechanism and an existing source annotation. This is refinement of the same transport step, not a new process. Proposed replacements: calcium ion import across plasma membrane Supporting Evidence: GO_REF:0000002 file:human/CACNA1C/CACNA1C-uniprot.txt |
| GO:0006936 muscle contraction | IEA GO_REF:0000117 | ACCEPT | Summary: CaV1.2 calcium entry contributes directly to muscle contraction. Reason: The broad ARBA process is independently supported by cardiac excitation-contraction coupling and native arterial channel physiology. Alpha1C performs the calcium-entry step that triggers contractile signaling, while ryanodine receptors release stored calcium and the contractile machinery generates force. Supporting Evidence: GO_REF:0000117 file:human/CACNA1C/CACNA1C-uniprot.txt |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | IDA PMID:12130699 Effects of methylmercury on human neuronal L-type calcium ch... | ACCEPT | Summary: Opening of alpha1C raises cytosolic calcium through extracellular influx. Reason: PMID:12130699 directly characterizes a recombinant calcium-channel preparation, although its reported current measurements use barium as charge carrier. Independent calcium-selectivity and influx evidence support the existing positive-cytosolic-calcium assertion without misdescribing that particular recording solution. Supporting Evidence: file:human/CACNA1C/CACNA1C-uniprot.txt |
| GO:0007507 heart development | IMP PMID:15454078 Ca(V)1.2 calcium channel dysfunction causes a multisystem di... | KEEP AS NON CORE | Summary: Cardiac development is a supported contextual role of altered CaV1.2 signaling. Reason: PMID:15454078 reports congenital cardiac abnormalities in Timothy syndrome and establishes the causal channel defect. Retain the curator-assigned developmental process as non-core, distinguishing developmental consequences of altered calcium signaling from the channel's direct electrical and contractile function. No new morphogenetic mechanism is asserted. Supporting Evidence: |
| GO:0008331 high voltage-gated calcium channel activity | IBA GO_REF:0000033 | ACCEPT | Summary: The L-type alpha1C pore has high-voltage-gated calcium-channel activity. Reason: The PTN001295293 PAINT inference agrees with human L-type channel experiments; target self-inclusion in WITH/FROM is not circular, and exact node placement was not independently reconstructed. The official GO:0008331 scope includes L-type channels. |
| GO:0008331 high voltage-gated calcium channel activity | IDA PMID:15454078 Ca(V)1.2 calcium channel dysfunction causes a multisystem di... | ACCEPT | Summary: The L-type alpha1C pore has high-voltage-gated calcium-channel activity. Reason: PMID:15454078 directly compares WT and G406R L-type currents and voltage-dependent inactivation. The official GO:0008331 scope includes L-type channels. Supporting Evidence: PMID:15454078 nearly complete loss of voltage-dependent channel inactivation |
| GO:0008331 high voltage-gated calcium channel activity | IEA GO_REF:0000117 | ACCEPT | Summary: The L-type alpha1C pore has high-voltage-gated calcium-channel activity. Reason: The ARBA classification agrees with independently demonstrated human L-type channel behavior. The official GO:0008331 scope includes L-type channels. |
| GO:0008331 high voltage-gated calcium channel activity | TAS PMID:11576544 Skeletal and cardiac ryanodine receptors bind to the Ca(2+)-... | ACCEPT | Summary: The L-type alpha1C pore has high-voltage-gated calcium-channel activity. Reason: The complete PMID:11576544 abstract concerns alpha1C C-terminal binding to ryanodine receptors; independent human currents establish the high-voltage activity. Preserve its original contributes_to qualifier, while the combined evidence identifies alpha1C as the pore-forming subunit. The official GO:0008331 scope includes L-type channels. |
| GO:0010881 regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion | ISS GO_REF:0000024 | ACCEPT | Summary: Calcium entry through CaV1.2 triggers stored-calcium release that regulates cardiac contraction. Reason: The existing ortholog-transfer assertion fits the independently established cardiac calcium-induced-calcium-release mechanism. PMID:11576544 reports alpha1C-region/RyR binding, while the complete PMID:34072954 review abstract describes the functional dyadic relationship. Alpha1C supplies trigger calcium; RyR2 releases sarcoplasmic-reticulum calcium. The source is not represented as proof that alpha1C itself forms the stored-calcium-release pore. Supporting Evidence: GO_REF:0000024 file:human/CACNA1C/CACNA1C-uniprot.txt |
| GO:0010881 regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion | TAS PMID:11576544 Skeletal and cardiac ryanodine receptors bind to the Ca(2+)-... | ACCEPT | Summary: Calcium entry through CaV1.2 triggers stored-calcium release that regulates cardiac contraction. Reason: The existing TAS assertion fits the independently established cardiac calcium-induced-calcium-release mechanism. PMID:11576544 reports alpha1C-region/RyR binding, while the complete PMID:34072954 review abstract describes the functional dyadic relationship. Alpha1C supplies trigger calcium; RyR2 releases sarcoplasmic-reticulum calcium. The source is not represented as proof that alpha1C itself forms the stored-calcium-release pore. |
| GO:0014069 postsynaptic density | IDA PMID:14140941 [A FORM OF TACHYCARDIA CAUSED BY DIGITALIS (PAROXYSMAL AURIC... | ACCEPT | Summary: Postsynaptic CaV1.2 localization is independently supported despite the unresolved original citation. Reason: The preserved PMID:14140941 record resolves to a 1964 tachycardia paper with no accessible abstract, and its target postsynaptic evidence was not verified. Independently, PMID:15140941 reports native rat postsynaptic complexes and CaV1.2/CaBP1 localization; the human UniProt record carries the conserved postsynaptic location. Retain the broad biological location with explicit independent support rather than claiming that the 1964 paper or an official PMID remapping was verified. Supporting Evidence: PMID:15140941 postsynaptic density fractions purified from rat brain file:human/CACNA1C/CACNA1C-uniprot.txt |
| GO:0014069 postsynaptic density | IEA GO_REF:0000117 | ACCEPT | Summary: The broad postsynaptic-density mapping agrees with independent channel-complex evidence. Reason: The ARBA location is corroborated by the native rat postsynaptic CaV1.2/CaBP1 experiments in PMID:15140941 and the conserved target localization. Human recombinant binding experiments are distinct from native rat subcellular localization; neither is described as an endogenous human brain image. |
| GO:0016020 membrane | IDA PMID:8392192 Cloning, chromosomal localization, and functional expression... | MODIFY | Summary: The broad membrane location can be refined to plasma membrane. Reason: Human alpha1C functional expression and direct surface measurements establish plasma membrane more specifically than the source membrane term. This does not exclude intracellular biosynthetic or recycling pools, and the original machine term remains unchanged. Proposed replacements: plasma membrane |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: The broad membrane location can be refined to plasma membrane. Reason: Human alpha1C functional expression and direct surface measurements establish plasma membrane more specifically than the source membrane term. This does not exclude intracellular biosynthetic or recycling pools, and the original machine term remains unchanged. Proposed replacements: plasma membrane |
| GO:0030018 Z disc | ISS GO_REF:0000024 | UNDECIDED | Summary: The precise Z-disc location remains unresolved in this assessment. Reason: The exact rat P22002 ortholog-transfer assertion is preserved. Available target evidence establishes sarcolemma, T-tubules and dyadic channel clusters, but these are not automatically identical to the Z disc. The donor localization experiment resolving this fine compartment was not inspected, so this is an access limitation rather than a claim of incorrect orthology. Supporting Evidence: GO_REF:0000024 file:human/CACNA1C/CACNA1C-uniprot.txt |
| GO:0030315 T-tubule | IEA GO_REF:0000044 | ACCEPT | Summary: Cardiac CaV1.2 occupies the sarcolemmal and T-tubule membrane system. Reason: The UniProt subcellular-location mapping agrees with cardiac dyadic channel organization described in the complete PMID:34072954 review abstract and the curated target record. This is a muscle-cell context, not a claim that all expressing cells possess T-tubules. |
| GO:0030425 dendrite | IEA GO_REF:0000044 | ACCEPT | Summary: Neuronal CaV1.2 occupies dendritic membranes. Reason: The UniProt mapping is corroborated by the dendritic/postsynaptic channel-complex observations in PMID:15140941. Native rat neuronal localization supports the conserved target placement; a human endogenous dendritic image was not independently inspected. |
| GO:0035115 embryonic forelimb morphogenesis | IMP PMID:15454078 Ca(V)1.2 calcium channel dysfunction causes a multisystem di... | KEEP AS NON CORE | Summary: Limb morphogenesis is retained as a contextual developmental role. Reason: PMID:15454078 reports congenital syndactyly in Timothy syndrome and selected primary text places Cacna1c expression in developing mouse digits. Retain the existing experimental curation as non-core while distinguishing the developmental phenotype from direct proof of a particular alpha1C-controlled morphogenetic step. Supporting Evidence: PMID:15454078 webbing of fingers and toes |
| GO:0042383 sarcolemma | IEA GO_REF:0000044 | ACCEPT | Summary: Cardiac CaV1.2 occupies the sarcolemmal and T-tubule membrane system. Reason: The UniProt subcellular-location mapping agrees with cardiac dyadic channel organization described in the complete PMID:34072954 review abstract and the curated target record. This is a muscle-cell context, not a claim that all expressing cells possess T-tubules. |
| GO:0042391 regulation of membrane potential | IEA GO_REF:0000117 | ACCEPT | Summary: Voltage-gated calcium conductance contributes to membrane potential. Reason: The broad ARBA inference agrees with direct human alpha1C currents and altered cardiac action potentials in human induced-pluripotent-stem-cell cardiomyocytes. The current changes voltage through ion movement rather than through a separate voltage-regulatory enzyme. |
| GO:0043010 camera-type eye development | IMP PMID:15454078 Ca(V)1.2 calcium channel dysfunction causes a multisystem di... | UNDECIDED | Summary: The specific eye-development assignment is not resolved by the inspected clinical and expression evidence. Reason: PMID:15454078 reports ocular abnormalities in the multisystem phenotype, and selected primary text describes developing mouse eye expression. The official term concerns progression of the eye toward its mature structure. A target-specific developmental assay or complete source argument resolving that process was not inspected; expression and clinical myopia are not equated with a demonstrated developmental step, but they also do not refute the curator's assertion. Supporting Evidence: |
| GO:0043204 perikaryon | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: A neuronal cell-body pool is retained as a broader channel location. Reason: The exact UniProt mapping or rat P22002 transfer is preserved. The curated target record places alpha1C in perikarya as well as dendrites and postsynaptic membranes. The original donor cell-body images were not independently re-examined; retain the established broad neuronal distribution without inventing a distinct cell-body-specific mechanism. Supporting Evidence: GO_REF:0000044 file:human/CACNA1C/CACNA1C-uniprot.txt |
| GO:0043204 perikaryon | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A neuronal cell-body pool is retained as a broader channel location. Reason: The exact UniProt mapping or rat P22002 transfer is preserved. The curated target record places alpha1C in perikarya as well as dendrites and postsynaptic membranes. The original donor cell-body images were not independently re-examined; retain the established broad neuronal distribution without inventing a distinct cell-body-specific mechanism. Supporting Evidence: GO_REF:0000024 file:human/CACNA1C/CACNA1C-uniprot.txt |
| GO:0045762 positive regulation of adenylate cyclase activity | ISS GO_REF:0000024 | UNDECIDED | Summary: The direction and context of adenylate-cyclase regulation remain unresolved. Reason: The exact Q01815-based ISS assertion is retained. Channel regulation by cAMP/PKA does not by itself demonstrate the reverse assertion that alpha1C positively regulates adenylate cyclase. A calcium-dependent feedback mechanism is biologically possible, but the specific donor assay and target evidence for the asserted direction were not inspected. This is not rejected merely because alpha1C lacks adenylate-cyclase catalytic activity. Supporting Evidence: GO_REF:0000024 file:human/CACNA1C/CACNA1C-uniprot.txt |
| GO:0045933 positive regulation of muscle contraction | NAS PMID:34072954 Mechanisms and Regulation of Cardiac Ca(V)1.2 Trafficking. | ACCEPT | Summary: CaV1.2 promotes contraction by supplying trigger calcium. Reason: The complete PMID:34072954 abstract describes CaV1.2 entry triggering RyR2-dependent calcium release and cardiac contraction. This is a narrative review, consistent with its NAS provenance; it is not presented as a new isolated contraction experiment. Independent arterial channel physiology corroborates the broader muscle context. |
| GO:0048513 animal organ development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Broad developmental consequences are retained outside the channel core. Reason: The ARBA inference is compatible with multisystem congenital phenotypes and developmental expression described in PMID:15454078. It is retained at this broad contextual scope without asserting a specific morphogenetic activity or manufacturing another process annotation from disease severity. |
| GO:0048731 system development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Broad developmental consequences are retained outside the channel core. Reason: The ARBA inference is compatible with multisystem congenital phenotypes and developmental expression described in PMID:15454078. It is retained at this broad contextual scope without asserting a specific morphogenetic activity or manufacturing another process annotation from disease severity. |
| GO:0051393 alpha-actinin binding | IPI PMID:17110593 Molecular coupling of a Ca2+-activated K+ channel to L-type ... | KEEP AS NON CORE | Summary: Alpha-actinin-2 physically couples CaV1.2 to a cardiac channel microdomain. Reason: PMID:17110593 explicitly reports CaV1.2 and CaV1.3 association with alpha-actinin-2 in cardiac myocytes, supporting the curated P35609 interaction. Retain alpha-actinin binding as non-core. The highlighted knockout physiology concerns CaV1.3 and is not transferred to CACNA1C; the abstract also distinguishes the alpha-actinin bridge from direct SK2βCaV1.2 binding. Full target-specific Methods were inaccessible. Supporting Evidence: |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | MODIFY | Summary: The broad transport inference can be refined to calcium import across plasma membrane. Reason: Human alpha1C directly conducts inward calcium current. The verified GO:0098703 definition specifies calcium movement from outside the cell into the cytosol across plasma membrane, matching the target mechanism and an existing source annotation. This is refinement of the same transport step, not a new process. Proposed replacements: calcium ion import across plasma membrane Supporting Evidence: GO_REF:0000002 file:human/CACNA1C/CACNA1C-uniprot.txt |
| GO:0060402 calcium ion transport into cytosol | ISS GO_REF:0000024 | ACCEPT | Summary: Alpha1C directly imports extracellular calcium into the cytosol. Reason: The ortholog-transfer assertion is independently substantiated by human channel expression and calcium-selective pore experiments. The exact donor experiment was not independently reconstructed. The original reference and provenance remain unchanged. Supporting Evidence: GO_REF:0000024 file:human/CACNA1C/CACNA1C-uniprot.txt |
| GO:0060402 calcium ion transport into cytosol | TAS PMID:19095005 New molecular components supporting ryanodine receptor-media... | ACCEPT | Summary: Alpha1C directly imports extracellular calcium into the cytosol. Reason: The TAS assertion is independently substantiated by human channel expression and calcium-selective pore experiments. PMID:19095005 is a review emphasizing junctophilin/TRIC/RyR machinery; its complete abstract is not treated as a new isolated alpha1C transport assay. The original reference and provenance remain unchanged. |
| GO:0061337 cardiac conduction | IMP PMID:24728418 Long QT syndrome type 8: novel CACNA1C mutations causing QT ... | ACCEPT | Summary: CaV1.2 current contributes to cardiac electrical propagation and rhythm. Reason: PMID:24728418 couples clinical long-QT phenotypes to functional human channel changes. The existing broad conduction process is supported by the channel's direct contribution to cardiomyocyte depolarizing current, without assigning intercellular gap-junction pore activity. |
| GO:0061577 calcium ion transmembrane transport via high voltage-gated calcium channel | IDA PMID:15454078 Ca(V)1.2 calcium channel dysfunction causes a multisystem di... | ACCEPT | Summary: CaV1.2 opening mediates high-voltage calcium entry into the cytosol. Reason: PMID:15454078 directly tests WT and G406R L-type currents. The work performed by alpha1C is transmembrane ion movement. |
| GO:0061577 calcium ion transmembrane transport via high voltage-gated calcium channel | IEA GO_REF:0000117 | ACCEPT | Summary: CaV1.2 opening mediates high-voltage calcium entry into the cytosol. Reason: The ARBA mapping agrees with target L-type channel recordings. The work performed by alpha1C is transmembrane ion movement. |
| GO:0061577 calcium ion transmembrane transport via high voltage-gated calcium channel | IMP PMID:30023270 A novel CACNA1C mutation identified in a patient with Timoth... | ACCEPT | Summary: CaV1.2 opening mediates high-voltage calcium entry into the cytosol. Reason: The actual PMID:30023270 body reports S643F with both reduced peak current and increased persistent/window-current features. The work performed by alpha1C is transmembrane ion movement. |
| GO:0061577 calcium ion transmembrane transport via high voltage-gated calcium channel | IMP PMID:30172029 A pore-localizing CACNA1C-E1115K missense mutation, identifi... | ACCEPT | Summary: CaV1.2 opening mediates high-voltage calcium entry into the cytosol. Reason: The complete PMID:30172029 abstract describes an E1115K mutant with nonselective monovalent conductance. This is a mutant selectivity change, not evidence that the WT calcium-channel annotation is false. The work performed by alpha1C is transmembrane ion movement. |
| GO:0061577 calcium ion transmembrane transport via high voltage-gated calcium channel | IMP PMID:30513141 Expanding clinical phenotype in CACNA1C related disorders: F... | ACCEPT | Summary: CaV1.2 opening mediates high-voltage calcium entry into the cytosol. Reason: PMID:30513141 is a clinical/genetic report with structural interpretation; its inspected text does not provide direct electrophysiology. Retain the broadly correct calcium-influx assertion through independent target evidence and curator deference, not an invented current assay in that paper. The work performed by alpha1C is transmembrane ion movement. |
| GO:0061577 calcium ion transmembrane transport via high voltage-gated calcium channel | IMP PMID:34163037 Phenotypic expansion of CACNA1C-associated disorders to incl... | ACCEPT | Summary: CaV1.2 opening mediates high-voltage calcium entry into the cytosol. Reason: PMID:34163037 includes a human L614R construct in HEK cells and other variants tested in a mouse channel construct with rat auxiliaries. The species and construct mixture is explicit. The indexed official correction adds an omitted author middle initial. The work performed by alpha1C is transmembrane ion movement. |
| GO:0070588 calcium ion transmembrane transport | IDA PMID:15454078 Ca(V)1.2 calcium channel dysfunction causes a multisystem di... | ACCEPT | Summary: Alpha1C directly mediates transmembrane calcium movement. Reason: PMID:15454078 directly characterizes L-type WT and mutant currents. |
| GO:0070588 calcium ion transmembrane transport | IDA PMID:27481713 The Ξ±2Ξ΄-1 subunit remodels CaV1.2 voltage sensors and allows... | ACCEPT | Summary: Alpha1C directly mediates transmembrane calcium movement. Reason: PMID:27481713 tests human alpha1C-77 with auxiliary subunits in Xenopus oocytes, using voltage-clamp fluorometry and barium currents to probe alpha2delta-dependent activation. The recording ion is distinguished from the established physiological calcium flux. Supporting Evidence: PMID:27481713 allowing Ca influx within the range of physiological membrane potentials file:human/CACNA1C/CACNA1C-uniprot.txt |
| GO:0070588 calcium ion transmembrane transport | IEA GO_REF:0000002 | ACCEPT | Summary: Alpha1C directly mediates transmembrane calcium movement. Reason: The InterPro inference agrees with human channel-expression and selectivity experiments. |
| GO:0070588 calcium ion transmembrane transport | IMP PMID:24728418 Long QT syndrome type 8: novel CACNA1C mutations causing QT ... | ACCEPT | Summary: Alpha1C directly mediates transmembrane calcium movement. Reason: PMID:24728418 measures functional WT and long-QT-associated channel changes. |
| GO:0086002 cardiac muscle cell action potential involved in contraction | IMP PMID:15454078 Ca(V)1.2 calcium channel dysfunction causes a multisystem di... | ACCEPT | Summary: The depolarizing L-type current couples cardiac action potentials to contraction. Reason: PMID:15454078 establishes abnormal channel inactivation in Timothy syndrome. The existing process is independently explained by trigger calcium entering through CaV1.2 and activating RyR-mediated release during excitation-contraction coupling; it is not inferred solely from syndrome severity. |
| GO:0086007 voltage-gated calcium channel activity involved in cardiac muscle cell action potential | IMP PMID:15454078 Ca(V)1.2 calcium channel dysfunction causes a multisystem di... | ACCEPT | Summary: CaV1.2 provides voltage-gated calcium-channel activity during cardiac action potentials. Reason: The original enables qualifier is preserved. Functional human channel measurements in the cited cardiac-variant study and independent human cardiomyocyte evidence establish this molecular activity. Clinical association strength is not conflated with whether alpha1C carries calcium current. |
| 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... | ACCEPT | Summary: CaV1.2 provides voltage-gated calcium-channel activity during cardiac action potentials. Reason: The original contributes_to qualifier is preserved. Functional human channel measurements in the cited cardiac-variant study and independent human cardiomyocyte evidence establish this molecular activity. Clinical association strength is not conflated with whether alpha1C carries calcium current. |
| GO:0086012 membrane depolarization during cardiac muscle cell action potential | IMP PMID:15454078 Ca(V)1.2 calcium channel dysfunction causes a multisystem di... | ACCEPT | Summary: Inward L-type calcium current contributes to cardiac action-potential depolarization. Reason: PMID:15454078 demonstrates prolonged channel opening through loss of voltage-dependent inactivation. Independent human cardiomyocyte evidence links alpha1C perturbation to action-potential prolongation. The annotation concerns the depolarizing channel current, not the initial sodium-channel upstroke in every cardiac cell. |
| GO:0086045 membrane depolarization during AV node cell action potential | IMP PMID:26253506 Identification and Functional Characterization of a Novel CA... | UNDECIDED | Summary: The AV-node-specific assignment remains more precise than the inspected functional evidence. Reason: PMID:26253506 explicitly reports clinical first-degree AV block in affected individuals, so AV evidence is not absent. Its inspected Methods/Results characterize human R518C/H channels in HEK293 cells and surface fluorescence, while the verified GO term requires the AV-node-cell action-potential context. The complete supplementary material and a source experiment resolving that cell-specific function were not inspected. Preserve the experimental assertion as uncertain rather than generalizing heterologous recordings or denying the clinical observation. Supporting Evidence: |
| GO:0086056 voltage-gated calcium channel activity involved in AV node cell action potential | IMP PMID:26253506 Identification and Functional Characterization of a Novel CA... | UNDECIDED | Summary: The AV-node-specific assignment remains more precise than the inspected functional evidence. Reason: PMID:26253506 explicitly reports clinical first-degree AV block in affected individuals, so AV evidence is not absent. Its inspected Methods/Results characterize human R518C/H channels in HEK293 cells and surface fluorescence, while the verified GO term requires the AV-node-cell action-potential context. The complete supplementary material and a source experiment resolving that cell-specific function were not inspected. Preserve the experimental assertion as uncertain rather than generalizing heterologous recordings or denying the clinical observation. Supporting Evidence: |
| GO:0086064 cell communication by electrical coupling involved in cardiac conduction | TAS PMID:11576544 Skeletal and cardiac ryanodine receptors bind to the Ca(2+)-... | UNDECIDED | Summary: Intercellular electrical coupling is distinct from the intracellular excitation-contraction coupling inspected here. Reason: The official GO:0086064 definition concerns electrical current between adjacent cardiac cells through intercellular protein channels. The complete PMID:11576544 abstract instead reports alpha1C-region binding to ryanodine receptors, a mechanism within excitation-contraction coupling. Full text was unavailable in the normal cache and was not independently recovered, so the precise TAS assertion remains unresolved rather than being removed from an abstract-only comparison. Supporting Evidence: |
| GO:0086091 regulation of heart rate by cardiac conduction | IMP PMID:15454078 Ca(V)1.2 calcium channel dysfunction causes a multisystem di... | ACCEPT | Summary: CaV1.2 current participates directly in regulation of the heartbeat through cardiac conduction. Reason: The cited variant study combines cardiac rhythm phenotypes with functional alpha1C channel evidence. The broad process is independently supported by the inward current and human cardiomyocyte action-potential effects. No separate claim of gap-junction conductance or an assay in every specialized conduction-cell population is implied. |
| GO:0086091 regulation of heart rate by cardiac conduction | IMP PMID:15863612 Severe arrhythmia disorder caused by cardiac L-type calcium ... | ACCEPT | Summary: CaV1.2 current participates directly in regulation of the heartbeat through cardiac conduction. Reason: The cited variant study combines cardiac rhythm phenotypes with functional alpha1C channel evidence. The broad process is independently supported by the inward current and human cardiomyocyte action-potential effects. No separate claim of gap-junction conductance or an assay in every specialized conduction-cell population is implied. |
| GO:0086091 regulation of heart rate by cardiac conduction | IMP PMID:17224476 Loss-of-function mutations in the cardiac calcium channel un... | ACCEPT | Summary: CaV1.2 current participates directly in regulation of the heartbeat through cardiac conduction. Reason: The cited variant study combines cardiac rhythm phenotypes with functional alpha1C channel evidence. The broad process is independently supported by the inward current and human cardiomyocyte action-potential effects. No separate claim of gap-junction conductance or an assay in every specialized conduction-cell population is implied. |
| GO:0086091 regulation of heart rate by cardiac conduction | IMP PMID:26253506 Identification and Functional Characterization of a Novel CA... | ACCEPT | Summary: CaV1.2 current participates directly in regulation of the heartbeat through cardiac conduction. Reason: The cited variant study combines cardiac rhythm phenotypes with functional alpha1C channel evidence. The broad process is independently supported by the inward current and human cardiomyocyte action-potential effects. No separate claim of gap-junction conductance or an assay in every specialized conduction-cell population is implied. |
| GO:0098703 calcium ion import across plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: The conserved alpha1C pore imports calcium across plasma membrane. Reason: The PTN001295293 PAINT assertion agrees with direct human channel function. A short donor list including a fungal channel does not by itself undermine a curated ancestral-node inference. Exact node placement was not reconstructed; the human target independently performs the transport step. Supporting Evidence: GO_REF:0000033 file:human/CACNA1C/CACNA1C-uniprot.txt |
| GO:0098839 postsynaptic density membrane | IEA GO_REF:0000044 | ACCEPT | Summary: CaV1.2 is associated with the postsynaptic membrane compartment. Reason: The original UniProt mapping or rat ortholog transfer agrees with native rat postsynaptic CaV1.2/CaBP1 observations in PMID:15140941 and the curated target localization. The neuronal source boundary is preserved; recombinant interaction assays are not described as endogenous human postsynaptic imaging. |
| GO:0098839 postsynaptic density membrane | ISS GO_REF:0000024 | ACCEPT | Summary: CaV1.2 is associated with the postsynaptic membrane compartment. Reason: The original UniProt mapping or rat ortholog transfer agrees with native rat postsynaptic CaV1.2/CaBP1 observations in PMID:15140941 and the curated target localization. The neuronal source boundary is preserved; recombinant interaction assays are not described as endogenous human postsynaptic imaging. |
| GO:0098911 regulation of ventricular cardiac muscle cell action potential | IMP PMID:15454078 Ca(V)1.2 calcium channel dysfunction causes a multisystem di... | ACCEPT | Summary: CaV1.2 gating regulates the ventricular cardiac action potential. Reason: The original channel-variant study is supported independently by human R518C induced-pluripotent-stem-cell cardiomyocyte action-potential prolongation in PMID:31430211 and established cardiac L-type-current physiology. Heterologous current assays and patient ECG findings remain distinct from direct native ventricular recordings in the original paper. Supporting Evidence: file:human/CACNA1C/CACNA1C-uniprot.txt |
| GO:0098911 regulation of ventricular cardiac muscle cell action potential | IMP PMID:26253506 Identification and Functional Characterization of a Novel CA... | ACCEPT | Summary: CaV1.2 gating regulates the ventricular cardiac action potential. Reason: The original channel-variant study is supported independently by human R518C induced-pluripotent-stem-cell cardiomyocyte action-potential prolongation in PMID:31430211 and established cardiac L-type-current physiology. Heterologous current assays and patient ECG findings remain distinct from direct native ventricular recordings in the original paper. Supporting Evidence: file:human/CACNA1C/CACNA1C-uniprot.txt |
| GO:0098912 membrane depolarization during atrial cardiac muscle cell action potential | IMP PMID:17224476 Loss-of-function mutations in the cardiac calcium channel un... | UNDECIDED | Summary: The specifically atrial action-potential assignment is not resolved by the inspected source. Reason: PMID:17224476 reports clinical ECG phenotypes and human channel currents in CHO-K1 cells, including trafficking and loss-of-current findings. Its complete abstract and inspected material do not establish which atrial-cell experiment underlies this fine annotation; full source-specific atrial physiology was not examined. The broadly correct cardiac calcium-channel function is accepted separately, without treating the more precise source assertion as disproven. Supporting Evidence: |
| GO:1990454 L-type voltage-gated calcium channel complex | IDA PMID:15454078 Ca(V)1.2 calcium channel dysfunction causes a multisystem di... | ACCEPT | Summary: Alpha1C is the pore-forming member of the L-type calcium-channel complex. Reason: The existing L-type complex term matches direct human alpha1C functional assembly with beta and alpha2delta subunits. PMID:27481713 resolves auxiliary-subunit modulation of human channel voltage sensors in a defined expression system. This supports membership without requiring the same auxiliary isoforms in every tissue. |
| GO:1990454 L-type voltage-gated calcium channel complex | IEA GO_REF:0000117 | ACCEPT | Summary: Alpha1C is the pore-forming member of the L-type calcium-channel complex. Reason: The existing L-type complex term matches direct human alpha1C functional assembly with beta and alpha2delta subunits. PMID:27481713 resolves auxiliary-subunit modulation of human channel voltage sensors in a defined expression system. This supports membership without requiring the same auxiliary isoforms in every tissue. |
| 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: Alpha1C is the pore-forming member of the L-type calcium-channel complex. Reason: The existing L-type complex term matches direct human alpha1C functional assembly with beta and alpha2delta subunits. PMID:27481713 resolves auxiliary-subunit modulation of human channel voltage sensors in a defined expression system. This supports membership without requiring the same auxiliary isoforms in every tissue. |
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Download this section (compressed HTML)Q: What is the verified source for the postsynaptic-density annotation attributed to PMID:14140941, and can the apparent association with the separately verified PMID:15140941 be resolved without changing the preserved original GOA reference?
Q: Which experiments specifically support the AV-node and atrial-cell action-potential annotations beyond clinical conduction phenotypes and heterologous channel recordings?
Q: Which developmental cell populations and channel-mediated steps account for the immune, eye and limb phenotypes associated with altered CACNA1C gating?
Q: Which donor experiments establish positive adenylate-cyclase regulation and Z-disc localization, and which of the 37 named human splice products were tested?
Experiment: Compare defined human splice products in matched cardiac and neuronal cellular contexts, separating surface channel abundance, calcium-dependent and voltage-dependent inactivation, and downstream physiology with independently validated localization assays.
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