CACNA1E

Summary: CaV2.3 is a high-voltage-activated calcium channel.

Reason: The InterPro ion-transport-domain mapping captures a real channel activity but leaves its transported ion and gating mechanism unspecified. Human alpha1E expression produces high-voltage-activated calcium-channel currents in two independent studies. Refine this general molecular function to the existing high voltage-gated calcium channel activity term.

Proposed replacements: high voltage-gated calcium channel activity

Summary: Human alpha1E generates voltage-dependent channel currents.

Reason: The original study expressed a human brain alpha1E clone in Xenopus oocytes and measured inward barium currents with voltage-dependent activation and inactivation. Barium was the electrophysiological charge carrier; this supports a calcium-channel molecular function rather than a separate physiological barium-transport role. The 2312-residue historical clone is not silently substituted for the current 2313-residue canonical sequence.

Summary: Human alpha1E reconstitution establishes calcium-channel activity.

Reason: The original abstract explicitly reports human alpha1E expression in HEK293 cells and Xenopus oocytes, producing high-voltage-activated calcium currents. The same paper also studies mouse cDNAs; that mixed-species scope does not invalidate the stated human channel experiment. Retain the source activity and evidence code.

Summary: The electronic channel-activity mapping agrees with human functional assays.

Reason: The source combines a named ARBA rule and calcium-channel InterPro domains. Independently measured human alpha1E currents establish voltage-gated calcium conductance. The broad but informative channel term is valid even though the high-voltage child is also present; no assumption about an uninspected rule donor is needed.

Summary: Disease-variant electrophysiology supports CaV2.3 channel function.

Reason: The source reports functional testing of several alpha1E S6 substitutions and a domain-II S4-S5-linker substitution, with altered activation, inactivation or current density. Those channel measurements support the molecular function independently of the clinical phenotype. Gain of function applies to the tested variants and must not be generalized to every CACNA1E allele.

Summary: The cited characterization directly establishes the channel activity.

Reason: Human alpha1E produces calcium currents in heterologous cells, with current amplitude enhanced by coexpression of neuronal auxiliary subunits. Retain this independently curated TAS assertion alongside the IDA assertion from the same paper; duplicate terms with different source assertions are legitimate.

Summary: The EF-hand calcium-binding inference lacks a directly inspected binding assay.

Reason: This electronic assertion originates from the EF-hand domain IPR002048. The original human cloning abstract describes two potential calcium-binding sites as predictions, and UniProt labels the corresponding binding residues with curator-inference evidence. Calcium permeation and calmodulin-mediated regulation do not, by themselves, verify calcium occupancy or affinity at this domain. Preserve the assertion as unresolved pending direct domain-specific evidence; do not declare the motif inactive or transfer the calcium-binding activity of a partner to the channel. The inspected human CaV2.3 structural and electrophysiological sections in PMID:36720859 do not resolve this EF-hand-specific uncertainty; pore permeation and a barium-current assay are not an EF-hand calcium-affinity measurement.

Summary: The presynaptic calcium-entry reaction places CaV2.3 at the plasma membrane.

Reason: The complete human Reactome summary describes calcium entering a presynaptic neuron across its membrane and explicitly includes R-type channels. This agrees with the transmembrane alpha1E pore and human channel reconstitution. The source is a curated reaction narrative rather than an independently inspected localization image.

Summary: The beta-cell calcium-entry reaction supports plasma-membrane localization.

Reason: The complete Reactome summary explicitly includes human CaV2.3 among voltage-gated calcium channels supporting beta-cell secretion and describes calcium movement across the plasma membrane. Retain the location without treating every statement about CaV1.2/CaV1.3 or their syntaxin interaction as evidence about alpha1E.

Summary: Alpha1E is the pore-forming unit of a calcium-channel assembly.

Reason: The source IBA is assigned through PTN001295293. Human alpha1E currents are strongly enhanced by coexpressed alpha2 and beta subunits, independently corroborating the calcium-channel-complex role. The complete PAINT tree and alignment were not reconstructed, so no detailed node history is claimed. Neither donor count nor a different channel subtype among descendants is grounds to reject this supported assembly function. Independent human cryo-EM evidence in PMID:36720859 directly resolves alpha1E with alpha2delta1 and beta1, supporting complex membership; it does not establish every native tissue stoichiometry.

Summary: Calcium-channel domain assignments support complex membership.

Reason: The channel-specific InterPro source domains match the human alpha1E pore-forming subunit. Functional coexpression with auxiliary alpha2 and beta subunits independently supports membership in the calcium-channel complex. A fixed auxiliary-subunit composition across all tissues is not implied. Independent human cryo-EM evidence in PMID:36720859 directly resolves alpha1E with alpha2delta1 and beta1, supporting complex membership; it does not establish every native tissue stoichiometry.

Summary: The original study demonstrates functional association with auxiliary subunits.

Reason: The human expression study reports a large increase in alpha1E current amplitude when neuronal alpha2 and beta subunits are coexpressed. This supports the curated channel-complex annotation while allowing alpha1E alone to produce currents; it does not require every auxiliary subunit for pore formation. Independent human cryo-EM evidence in PMID:36720859 directly resolves alpha1E with alpha2delta1 and beta1, supporting complex membership; it does not establish every native tissue stoichiometry.

Summary: The broad transport mapping can be resolved to calcium entry.

Reason: The generic ion-transport-domain assertion is correct but omits the demonstrated calcium selectivity and transmembrane direction in the physiological membrane context. Alpha1E itself supplies the conducting pore that admits extracellular calcium upon depolarization. Refine to the existing calcium ion import across plasma membrane term.

Proposed replacements: calcium ion import across plasma membrane

Summary: Presynaptic CaV2.3 calcium entry contributes directly to transmission.

Reason: The PTN000004141 IBA asserts an inherited synaptic role. Independent human Reactome synthesis explicitly includes R-type channels in the calcium-entry step triggering transmitter release, and the target disease study identifies CaV2.3 currents as initiating synaptic transmission. The channel performs the ion-entry step itself; this is not inferred solely from a neurological phenotype. The exact PAINT tree was not independently reconstructed.

Summary: The curated synaptic role is supported by the channel mechanism and independent pathway evidence.

Reason: The original cloning abstract directly establishes neuronal expression and human alpha1E conductance, but it does not expose a synaptic-release assay. Retain the TAS assertion with curator deference and independent Reactome support for the R-type calcium-entry step in transmitter release. Do not describe the heterologous expression study as a native human synapse experiment.

Summary: R-type CaV2.3 is a high-voltage-activated channel.

Reason: The PTN001295293 IBA agrees with two direct human alpha1E expression studies that explicitly classify its currents as high-voltage activated. Pharmacological resemblance to some low-voltage currents in the earlier paper does not make CaV2.3 a T-type channel. Target-specific functional evidence supports this term without reconstructing the full PAINT tree or judging support by donor number.

Summary: Plasma membrane is the supported specific membrane location.

Reason: The InterPro and UniProt subcellular-location mapping establishes a membrane protein but is less specific than the curated calcium-entry reactions and functional surface-channel expression. Refine membrane to plasma membrane; no organelle-membrane pool is inferred from this broad source.

Proposed replacements: plasma membrane

Summary: The experimentally measured channel is specifically a high-voltage calcium channel.

Reason: Functional assays of human CACNA1E variants measure alpha1E-mediated calcium-channel currents and their activation/inactivation properties. The monoatomic-cation-channel parent is valid but unnecessarily general for this identified R-type channel. Refine to high voltage-gated calcium channel activity without changing the experimental evidence code or attributing every mutant effect to wild-type protein.

Proposed replacements: high voltage-gated calcium channel activity

Summary: Retain the phylogenetically curated neuronal cell-body location.

Reason: The IBA through PTN000004144 records a somatic neuronal channel location, compatible with the neuronal alpha1E protein and its membrane conductance. No target-specific evidence of loss or exclusion from this compartment was found. The human cloning abstract establishes CNS expression, not a cell-body localization image; the more specific localization is retained as the PAINT curator assertion, with the full tree and donor microscopy not independently inspected.

Summary: Synaptic localization is consistent with the retained transmission role.

Reason: The logical-inference source derives location from the existing chemical-synaptic-transmission assertion. Independent Reactome synthesis places R-type calcium entry at the presynaptic neuron membrane. Retain the broad synapse location without upgrading it to an unobserved sub-synaptic compartment or claiming a gene-specific localization experiment from the pathway narrative.

Summary: The transmembrane transport is specifically calcium import.

Reason: The ion-transport-domain mapping captures a genuine transmembrane activity. Functional expression and the physiological calcium-entry reaction resolve the ion and inward direction across the plasma membrane. Refine this broad parent to the existing calcium-import term; the pore is not an ATP-driven calcium pump.

Proposed replacements: calcium ion import across plasma membrane

Summary: Calcium transmembrane transport is intrinsic to the alpha1E pore.

Reason: The two calcium-channel InterPro sources agree with human alpha1E-mediated calcium currents. The gene product performs transport itself, so this process is direct participation rather than a downstream response to changed calcium concentration.

Summary: CaV2.3 admits extracellular calcium into the cytosol.

Reason: The PTN001295293 IBA describes a conserved pore-mediated transport process that is independently supported by human alpha1E electrophysiology and the curated calcium-entry reactions. The presence of a distant fungal descendant among the source entities does not imply pairwise transfer or invalidate an ancestral transport function. No uninspected tree topology or source experiment is asserted.