CACNA1G

Summary: Regulated expression of a functional SAN channel does not establish participation in node development.

Reason: GO:0003163 concerns progression of the sinoatrial node from formation to a mature structure. The accessed publisher SAN section of PMID:26786210 distinguishes Isl1-dependent developmental regulators from ion channels for SAN function, including Cacna1g. Downregulation of the channel after loss of Isl1 establishes regulation within that program, not that the channel itself performs a step in node formation or maturation. The NAS developmental assertion therefore exceeds the cited mechanistic evidence. This judgment does not deny established pacemaker-current function or rule out a separately demonstrated developmental contribution.

Summary: CaV3.1 is specifically a low-voltage-activated calcium channel.

Reason: The InterPro ion-transport domain supports a channel, but human recombinant electrophysiology in PMID:10648811 and PMID:26715324 identifies the T-type calcium-selective activity more precisely.

Proposed replacements: low voltage-gated calcium channel activity

Summary: Human recombinant CaV3.1 supports the more specific low-voltage calcium-channel activity.

Reason: PMID:10648811 establishes T-type currents rather than an unspecified voltage-gated calcium current. The publisher corrigendum, DOI:10.1016/S0014-5793(00)01326-0, corrects the expressed cDNA to CaV3.1a without an erroneous 18-residue exon; it does not retract channel activity. Preserve the original fetched title and PMID.

Proposed replacements: low voltage-gated calcium channel activity

Summary: The domain-based voltage-gated calcium-channel assignment can be specified as T-type.

Reason: InterPro IPR002077/IPR005445 provide compatible channel-family evidence. Human channel recordings in PMID:26715324 establish low-voltage activation, supporting GO:0008332 rather than only its broader parent.

Proposed replacements: low voltage-gated calcium channel activity

Summary: The childhood-ataxia variants alter a T-type calcium channel.

Reason: PMID:29878067 reports slower inactivation and increased window current for the tested CACNA1G variants. These gain-of-function changes occur in CaV3.1 and do not convert its classification to a high-voltage calcium channel; use the low-voltage activity term.

Proposed replacements: low voltage-gated calcium channel activity

Summary: An intracellular pool of expressed CaV3.1 was observed in addition to surface localization.

Reason: PMID:26715324 reports diffuse cytoplasmic and plasma-membrane immunoreactivity for wild-type and mutant channels in transfected cells, using NaK-ATPase as a membrane marker. Retain the observed cytoplasmic distribution without treating it as soluble-channel activity or the principal functional location.

Summary: The automated cytoplasmic localization is consistent with the observed intracellular channel pool.

Reason: The combined ARBA/subcellular-location mapping is supported by the localization results in PMID:26715324. This broad intracellular distribution is distinct from the plasma membrane where calcium entry is measured.

Summary: CaV3.1 functions as a plasma-membrane calcium channel.

Reason: The localization analysis in PMID:26715324 detects wild-type and mutant CaV3.1 at the plasma membrane; whole-cell recordings demonstrate functional calcium currents. The tested recombinant-cell context is retained without claiming a native human tissue localization experiment.

Summary: The subcellular-location mapping identifies the membrane across which CaV3.1 conducts calcium.

Reason: UniProt cell-membrane annotation and the localization/current measurements in PMID:26715324 support this compartment. Plasma membrane is the appropriate core location for the inward calcium current.

Summary: The Reactome T-type-channel event is compatible with plasma-membrane CaV3.1.

Reason: The complete R-HSA-9700701 narrative includes CACNA1G among the T-type channels mediating calcium entry. The fetched narrative does not expose a full structured compartment inventory, so the precise localization is also corroborated by PMID:26715324 rather than inferred from drug indications.

Summary: The inherited complex-membership claim is unresolved without a demonstrated CaV3.1 channel assembly.

Reason: GO:0005891 requires a channel-forming protein complex; its GO:0032991 ancestor requires an assembly of multiple macromolecules functioning together. Autonomous CaV3.1 pore activity does not by itself establish such an assembly, and lack of mandatory auxiliary subunits does not prove that native complexes never occur. Caveolin-3 co-immunoprecipitation in PMID:21084288 supports scaffold association, not demonstrated membership of a stable channel-forming unit; that observation is not used as positive complex evidence. The PAINT assertion records PTN001295293, but its positive ancestral evidence and placement were not reconstructed. Unlike GO:0008331, which target-specific low-voltage recordings directly contradict, a generic complex can remain compatible with optional partners. Neither an HVA-like assembly nor loss of an ancestral assembly is established. Retain this row as UNDECIDED pending native-complex and ancestral-evidence review; donor number or identity is not the argument.

Summary: The domain mapping identifies a calcium-channel pore but does not settle its native complex membership.

Reason: GO:0005891 requires a channel-forming protein complex; its GO:0032991 ancestor requires an assembly of multiple macromolecules functioning together. Autonomous CaV3.1 pore activity does not by itself establish such an assembly, and lack of mandatory auxiliary subunits does not prove that native complexes never occur. Caveolin-3 co-immunoprecipitation in PMID:21084288 supports scaffold association, not demonstrated membership of a stable channel-forming unit; that observation is not used as positive complex evidence. InterPro:IPR002077 and InterPro:IPR005445 identify the channel architecture; they do not specify a verified CaV3.1 partner assembly in the evidence inspected. The unverified point is complex membership, not calcium conductance. Preserve the machine mapping and mark the review UNDECIDED pending direct assembly evidence.

Summary: The orthologous complex assertion requires the donor assembly evidence to be checked.

Reason: GO:0005891 requires a channel-forming protein complex; its GO:0032991 ancestor requires an assembly of multiple macromolecules functioning together. Autonomous CaV3.1 pore activity does not by itself establish such an assembly, and lack of mandatory auxiliary subunits does not prove that native complexes never occur. Caveolin-3 co-immunoprecipitation in PMID:21084288 supports scaffold association, not demonstrated membership of a stable channel-forming unit; that observation is not used as positive complex evidence. UniProtKB:Q5SUG4 is the recorded ISS donor. Its exact supporting native-complex experiment was not recovered; orthology alone cannot resolve the missing assembly information. UNDECIDED records that evidence gap without claiming paralog confusion or absence of a complex.

Summary: The cloning abstract establishes T-type channel function but leaves multiprotein assembly unverified.

Reason: The available PMID:9495342 abstract reports rat-brain cloning, Xenopus expression and human-gene mapping, establishing T-type channel identity. GO:0005891 additionally requires a channel-forming protein complex, not merely a functional pore polypeptide. The complete original paper was not recovered and its native-complex evidence cannot be adjudicated from the abstract. CaV3.1 activity without mandatory auxiliary subunits does not exclude optional native partners. Retain the TAS source unchanged and use UNDECIDED for complex membership; neither the organism in the title nor missing full text is used to allege misattribution.

Summary: The transported ion and direction can be specified as calcium entry across the plasma membrane.

Reason: The broad ion-transport domain mapping is biologically sound. Human CaV3.1 inward-current measurements in PMID:26715324 and the existing GO:0098703 assertion specify calcium import across the plasma membrane.

Proposed replacements: calcium ion import across plasma membrane

Summary: The high-voltage activity conflicts with the directly characterized low-voltage T-type channel.

Reason: GO:0008331 and GO:0008332 are distinct high- and low-voltage children of voltage-gated calcium-channel activity. The IBA records ancestral node PTN001295293, but the target-specific human recordings in PMID:10648811 and PMID:26715324 establish low-voltage activation. The issue is application of a high-voltage ancestral state to this T-type target, not the number or identity of extant donors. The full PAINT tree/node placement was not reconstructed, so no unverified evolutionary-loss scenario is asserted. Current PAINT places an IRD (NOT) for this term at PTN008457639 (2026-08-28), the CACNA1G/CACNA1H T-type channel clade, so this IBA is no longer propagated by PAINT and remains only in the cached GOA file. The IRD agrees with this verdict.

Proposed replacements: low voltage-gated calcium channel activity

Summary: CaV3.1 has low-voltage-activated calcium-channel activity.

Reason: Although PMID:21084288 foregrounds CaV3.2, its abstract explicitly describes CaV3.1 currents in transfected HEK293 cells and a comparison of caveolin-3 effects. The target is therefore present in the reported experiments; its established T-type activity is corroborated independently by PMID:26715324.

Summary: The SCA42-associated channel retains T-type identity while its gating is altered.

Reason: PMID:26456284 compares wild-type and R1715H human CaV3.1 in HEK293T cells. The mutation shifts activation toward more positive potentials; this is an altered low-voltage-channel gating phenotype rather than evidence that normal CACNA1G encodes a high-voltage channel.

Summary: Human CaV3.1 directly generates low-voltage-activated calcium currents.

Reason: PMID:26715324 records wild-type and mutant channels in HEK293T cells after a hyperpolarizing prepulse. Wild-type half-activation is about -57.5 mV and the R1715H construct is shifted toward more positive potentials. These results directly support T-type channel activity; the reporter is IRES-EGFP and is not described as a channel-GFP fusion.

Summary: The ARBA low-voltage calcium-channel assignment agrees with direct target experiments.

Reason: ARBA00091989 assigns the T-type molecular activity demonstrated for recombinant human CACNA1G in PMID:10648811, PMID:26456284 and PMID:26715324. No donor-count or circularity argument is required.

Summary: Plasma membrane is the supported functional membrane location.

Reason: The domain-based membrane annotation is correct but nonspecific. PMID:26715324 provides plasma-membrane immunolocalization and whole-cell currents, supporting the more informative GO:0005886 term.

Proposed replacements: plasma membrane

Summary: Inward CaV3.1 calcium current contributes directly to membrane-voltage behavior.

Reason: PMID:21084288 includes a CaV3.1 current comparison even though its strongest caveolin-dependent modulation is on CaV3.2. Retain the regulation-of-membrane-potential assertion as a direct consequence of voltage-dependent inward current, supported independently by CACNA1G gating experiments in PMID:26715324. Do not transfer the CaV3.2-specific PKA/caveolin regulation mechanism to CaV3.1.

Summary: The generic transmembrane-transport assignment can identify calcium import across the cell surface.

Reason: CaV3.1 is a calcium-selective channel conducting inward current across the plasma membrane (PMID:26715324). GO:0098703 states the transported ion, direction and membrane more precisely than the broad domain-derived term.

Proposed replacements: calcium ion import across plasma membrane

Summary: The calcium import occurs across the plasma membrane.

Reason: PMID:21084288 measures CaV3.1 current in HEK293 cells, and PMID:26715324 supplies target-specific cell-surface localization and inward calcium-current evidence. The existing GO:0098703 term specifies this import route without implying an organellar calcium channel.

Proposed replacements: calcium ion import across plasma membrane

Summary: The ARBA calcium-import annotation can specify the plasma membrane route.

Reason: The general import process is consistent with CaV3.1 physiology. Human localization and electrophysiology in PMID:26715324, together with the existing GO:0098703 annotation, support calcium ion import across plasma membrane.

Proposed replacements: calcium ion import across plasma membrane

Summary: CaV3.1 directly transports calcium through its membrane-spanning pore.

Reason: PMID:26456284 measures wild-type and R1715H calcium-channel currents in HEK293T cells. Calcium transmembrane transport is the physical activity being assayed, regardless of the disease allele altering its voltage dependence.

Summary: The electrophysiology demonstrates calcium movement across the membrane.

Reason: PMID:26715324 isolates calcium currents in HEK293T cells expressing wild-type or mutant CACNA1G. This is direct channel-mediated ion transport, not merely a downstream phenotype requiring the protein.

Summary: The calcium-channel family domains support calcium transmembrane transport.

Reason: InterPro IPR002077/IPR005445 identify the calcium-channel pore architecture; direct human current measurements in PMID:26715324 corroborate the inferred transport process.

Summary: Negative right-atrial evidence limits a working-myocyte claim; other contractile-cell contexts remain unresolved.

Reason: GO:0086002 concerns an action potential involved in contraction of that same cardiac muscle cell. PMID:16690884 supplies affirmative negative evidence for the sampled right-atrial myocytes: no detectable T-type current in wild-type or knockout cells and no altered atrial excitability after Cacna1g disruption. That result is not uncertainty about the atrium and does not support this annotation there. It also does not test all ventricular, developmental or disease-associated contractile-cell settings. The precise evidence behind ISS donor UniProtKB:Q5SUG4 and any applicable ventricular context remain unverified, so retain UNDECIDED for that residual scope. Nodal pacemaking is established separately and cannot substitute for a contraction-coupled action potential in the same working myocyte.

Summary: CaV3.1 contributes to sinoatrial pacemaker electrical activity.

Reason: The ISS source is UniProtKB:Q5SUG4. The mouse Cacna1g study PMID:16690884 reports loss of SAN T-type current, slower cellular pacemaking and reduced diastolic depolarization after gene disruption. The channel carries current contributing to this process; retain the tissue-specific orthology inference without calling it a direct human experiment.

Summary: CaV3.1 contributes to atrioventricular nodal electrical activity.

Reason: The ISS source is UniProtKB:Q5SUG4. Primary mouse studies PMID:16690884 and PMID:21406960 implicate CaV3.1 current in AV conduction and nodal pacemaking. PMID:21406960 distinguishes intermittent automaticity block and reduced maximal rates after CaV3.1 loss from the stronger absence of spontaneous activity after CaV1.3 loss.

Summary: CaV3.1 contributes to the sinoatrial electrical signal that drives atrial excitation.

Reason: The ISS source is UniProtKB:Q5SUG4. GO:0086015 SA-node action potential is part of GO:0086018 in the checked ontology; this signaling term therefore includes generation of the nodal electrical signal, not only gap-junction transfer. The CaV3.1 contribution to SAN current and pacemaking in PMID:16690884 supports the tissue-specific inference without assigning gap-junction activity.

Summary: The channel contributes to AV nodal electrical output in the conduction pathway.

Reason: The ISS source is UniProtKB:Q5SUG4. The checked ontology includes the AV-node action potential within AV-node-to-His signaling. Mouse current, conduction-delay and pacemaker findings in PMID:16690884 and PMID:21406960 support the nodal contribution. This does not make CaV3.1 the intercellular coupling pore or establish expression in bundle-of-His cells.

Summary: CaV3.1 calcium current supports AV nodal depolarization.

Reason: The ISS source is UniProtKB:Q5SUG4. Low-voltage inward current can contribute during the depolarizing trajectory, and the mouse AVNC experiments in PMID:21406960 identify its contribution to stable pacing and maximal stimulated rate. Preserve the context-specific inference without asserting that CaV3.1 alone generates every AV-node action potential.

Summary: CaV3.1 contributes depolarizing current during sinoatrial pacemaking.

Reason: The ISS source is UniProtKB:Q5SUG4. PMID:16690884 reports reduced diastolic depolarization slope in individual SAN cells lacking CaV3.1. This is direct current participation in nodal excitation, with human assignment retained as an orthology inference.

Summary: The voltage-gated calcium-channel activity has an AV nodal context.

Reason: The ISS source is UniProtKB:Q5SUG4. PMID:21406960 establishes a CaV3.1 contribution to mouse AVNC automaticity and high pacing rates. Retain this specialized activity as a context of the core low-voltage calcium conductance, rather than a second molecular mechanism.

Summary: The calcium-channel activity contributes to sinoatrial nodal excitation.

Reason: The ISS source is UniProtKB:Q5SUG4. PMID:16690884 connects the lost SAN T-type current to slower pacemaker activity. The specialized GO activity is consistent with that electrical role but remains an inferred human tissue context.

Summary: CaV3.1 modulates heart rate through nodal conduction and pacemaking.

Reason: The ISS source is UniProtKB:Q5SUG4. The bradycardia, prolonged SAN recovery and delayed AV conduction reported in the mouse Cacna1g study PMID:16690884 support this physiological role. Retain it as a tissue-specific outcome of inward calcium current, without implying that CACNA1G alone sets cardiac rhythm.

Summary: The automated scaffold-binding assignment is consistent with caveolin-3 association.

Reason: ARBA00034605 is corroborated by the CaV3.1 co-immunoprecipitation reported in PMID:21084288. The study does not show that caveolin-3 reduces CaV3.1 peak current; that effect is reported for CaV3.2. Retain scaffold association as an accessory context rather than the defining channel activity.

Summary: CaV3.1 associates with the scaffold caveolin-3.

Reason: PMID:21084288 explicitly reports CaV3.1 and caveolin-3 co-immunoprecipitation in the available abstract and Figure 1 caption. Direct N-terminal GST-pulldown binding and PKA modulation are described for CaV3.2, so those details are not transferred to CaV3.1. Retain the original IPI scaffold-binding assertion with its experimental association limit.

Summary: CaV3.1 mediates calcium entry from the extracellular space across the plasma membrane.

Reason: The IBA from PTN001295293 is consistent with human cell-surface localization and inward-current recordings in PMID:26715324. The ancestral inference is supported by target-specific transport biology; the small extant evidence list is not a reason to downgrade it.