CACNB3 encodes the beta3 auxiliary subunit of high voltage-activated calcium channels. It is a cytoplasmic protein built from an SH3 domain, a HOOK region and a catalytically inactive guanylate-kinase-like domain; the guanylate-kinase-like domain binds the alpha-interaction domain in the intracellular I-II loop of the pore-forming alpha1 subunit. By binding alpha1, beta3 increases channel surface expression and peak current and shifts the voltage dependence of activation and inactivation of L-type (Cav1) and N-type (Cav2.2) channels, so it controls calcium influx in neurons, smooth muscle and other excitable cells. The horse entry A0A5F5PZM5 is an alternative first-exon model of the gene whose conserved core is almost identical to human beta3.
Summary: Combined IEA (InterPro VDCC beta signatures) assigns pore activity to a subunit that has no pore.
Reason: CACNB3 is the cytoplasmic auxiliary beta subunit; the calcium-conducting pore is formed by the alpha1 subunit. The horse protein is the beta3 ortholog (99.78% core identity to human CACNB3 versus 63-74% to the other beta paralogs), and human beta3 modulates channel current amplitude and gating when coexpressed with alpha1. The correct molecular function is calcium channel regulator activity.
Over the shared core, A0A5F5PZM5 is 99.78% identical to human CACNB3 (P54284; 464/465 paired residues), against 63.36% to CACNB1 (Q02641), 65.09% to CACNB2 (Q08289) and 74.14% to CACNB4 (O00305).
Summary: Beta3 is a cytoplasmic subunit binding the intracellular alpha-interaction domain of alpha1.
Reason: UniProt SubCell mapping to cytoplasm. Human beta3 is a soluble cytoplasmic protein that docks on the intracellular I-II loop of alpha1, as resolved in the human Cav2.2 cryo-EM structure; the horse core is near-identical, so the location transfers.
Supporting Evidence:
file:human/CACNB3/CACNB3-uniprot.txt
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:34234349}.
Over the shared core, A0A5F5PZM5 is 99.78% identical to human CACNB3 (P54284; 464/465 paired residues), against 63.36% to CACNB1 (Q02641), 65.09% to CACNB2 (Q08289) and 74.14% to CACNB4 (O00305).
Summary: Family-wide PAINT assertion at PTN000930213; human beta3 is a structurally resolved subunit of Cav channel complexes.
Reason: The PAINT node covers all calcium-channel beta subunits and is seeded by experimental annotations of many members, including human CACNB3. Horse A0A5F5PZM5 is the beta3 ortholog and lies inside this clade. Human beta3 is a subunit of both Cav1 (L-type) and Cav2.2 (N-type) complexes.
Supporting Evidence:
file:human/CACNB3/CACNB3-uniprot.txt
CC -!- FUNCTION: Regulatory subunit of the voltage-gated calcium channel that CC gives rise to L-type calcium currents (PubMed:8119293).
Over the shared core, A0A5F5PZM5 is 99.78% identical to human CACNB3 (P54284; 464/465 paired residues), against 63.36% to CACNB1 (Q02641), 65.09% to CACNB2 (Q08289) and 74.14% to CACNB4 (O00305).
Summary: Consistent with the IBA row; beta3 is a subunit of voltage-gated calcium channel complexes.
Reason: Same claim as the IBA row. Human beta3 is resolved as an ancillary subunit in the Cav2.2 complex structure and assembles with L-type alpha1D in functional channels; the horse ortholog has an identical core.
Over the shared core, A0A5F5PZM5 is 99.78% identical to human CACNB3 (P54284; 464/465 paired residues), against 63.36% to CACNB1 (Q02641), 65.09% to CACNB2 (Q08289) and 74.14% to CACNB4 (O00305).
Summary: True but general; beta3 acts on transmembrane calcium influx through the channel, already captured by GO:0070588.
Reason: Beta3 contributes to calcium transport only as a regulatory subunit of the plasma-membrane channel complex, i.e. to calcium ion transmembrane transport (GO:0070588), a descendant that horse CACNB3 already carries. The PAINT inference itself is sound for this clade.
Propagation Review
Root cause:TERM SCOPING PROBLEM
Failure modes:GRANULARITY MISMATCH
Sources checked:
PANTHER:PTN000930213SUPPORTS TRANSFER
Family-wide calcium-channel beta node; the target horse beta3 lies inside it. Placement is sound; the parent process is true but less specific than transmembrane transport.
UniProtKB:P54284SUPPORTS TRANSFER
Human CACNB3, the ortholog of the target, is one of the experimental descendants grounding the node.
Over the shared core, A0A5F5PZM5 is 99.78% identical to human CACNB3 (P54284; 464/465 paired residues), against 63.36% to CACNB1 (Q02641), 65.09% to CACNB2 (Q08289) and 74.14% to CACNB4 (O00305).
Over the shared core, A0A5F5PZM5 is 99.78% identical to human CACNB3 (P54284; 464/465 paired residues), against 63.36% to CACNB1 (Q02641), 65.09% to CACNB2 (Q08289) and 74.14% to CACNB4 (O00305).
GO:0008331 high voltage-gated calcium channel activity
IBA GO_REF:0000033
MODIFY
Summary: PAINT propagated pore activity of the assembled channel to the beta subunit; the beta subunit regulates rather than conducts.
Reason: The PTN000930213 MF assertion is seeded by a single mouse beta subunit and states high voltage-gated calcium channel activity without a contributes_to qualifier. Beta subunits lack transmembrane segments and a pore; their activity is regulation of the HVA alpha1 subunit (current amplitude, voltage dependence, surface expression). The phylogenetic placement of the horse protein in the clade is not in question, only the term.
Propagation Review
Root cause:TERM SCOPING PROBLEM
Failure modes:ROLE CONFLATION
Sources checked:
PANTHER:PTN000930213SUPPORTS SOURCE BUT NOT TARGET
Node placement covers all beta subunits including the target; the asserted MF names the activity of the assembled channel pore rather than the beta-subunit regulatory activity.
MGI:MGI:102522SUPPORTS SOURCE BUT NOT TARGET
Single mouse beta-subunit seed; a channel-activity annotation on a beta subunit reflects coexpression with alpha1, which fits contributes_to or regulator activity.
Over the shared core, A0A5F5PZM5 is 99.78% identical to human CACNB3 (P54284; 464/465 paired residues), against 63.36% to CACNB1 (Q02641), 65.09% to CACNB2 (Q08289) and 74.14% to CACNB4 (O00305).
Summary: Projected from a human membrane-proteomics observation; beta3 is peripheral on the cytoplasmic face of membrane channel complexes.
Reason: Membrane association arises from binding to the membrane-embedded alpha1 subunit; beta3 has no transmembrane segment or known lipid anchor. The term is true at the level of resolution the source supports but is not the core location (which is the channel complex and cytoplasm).
Over the shared core, A0A5F5PZM5 is 99.78% identical to human CACNB3 (P54284; 464/465 paired residues), against 63.36% to CACNB1 (Q02641), 65.09% to CACNB2 (Q08289) and 74.14% to CACNB4 (O00305).
Summary: Beta3 participates in transmembrane calcium influx as a regulatory subunit of the channel complex.
Reason: Coexpression of human beta3 modulates voltage-dependent calcium channel currents, and beta3 is a structural subunit of the channel complex. Participation in calcium ion transmembrane transport as a channel-complex subunit is appropriate; horse core identity supports transfer.
Supporting Evidence:
file:human/CACNB3/CACNB3-uniprot.txt
CC -!- FUNCTION: Regulatory subunit of the voltage-gated calcium channel that CC gives rise to L-type calcium currents (PubMed:8119293).
Over the shared core, A0A5F5PZM5 is 99.78% identical to human CACNB3 (P54284; 464/465 paired residues), against 63.36% to CACNB1 (Q02641), 65.09% to CACNB2 (Q08289) and 74.14% to CACNB4 (O00305).
Summary: Beta3 assembles with L-type alpha1 subunits (Cav1.2, Cav1.3).
Reason: Human beta3a coexpressed with alpha1D and alpha2delta-1 forms functional L-type channels, and UniProt records beta3 in a CACNA1C complex. Beta3 is not L-type-exclusive (it is also in the Cav2.2 structure), but L-type membership is supported.
Supporting Evidence:
file:human/CACNB3/CACNB3-uniprot.txt
CC -!- FUNCTION: Regulatory subunit of the voltage-gated calcium channel that CC gives rise to L-type calcium currents (PubMed:8119293).
Over the shared core, A0A5F5PZM5 is 99.78% identical to human CACNB3 (P54284; 464/465 paired residues), against 63.36% to CACNB1 (Q02641), 65.09% to CACNB2 (Q08289) and 74.14% to CACNB4 (O00305).
Core Functions
Auxiliary beta3 subunit that binds the pore-forming alpha1 subunit of high voltage-activated calcium channels and regulates their surface expression, current amplitude and voltage-dependent gating.
Over the shared core, A0A5F5PZM5 is 99.78% identical to human CACNB3 (P54284; 464/465 paired residues), against 63.36% to CACNB1 (Q02641), 65.09% to CACNB2 (Q08289) and 74.14% to CACNB4 (O00305).
Q: Is the 49-residue alternative first exon of horse model A0A5F5PZM5 supported by transcript evidence, and does it alter beta3 modulation of inactivation as alternative N-termini do for other beta subunits?
External Prediction Reviews
These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.
Assessment of 1 ProtNLM GO predictions for the selected horse CACNB3 protein, using mammalian experimental findings and an explicit comparison of the horse sequence.
Prediction method: ProtNLM2 Β· Version: UniProt API snapshot 2026-09-08
Review rationale: Beta subunits regulate high voltage-activated calcium channel currents without forming the pore. Coexpression of human beta3 modulates voltage-dependent calcium channel activity (PMID:8119293), and rat beta3 coexpressed with a cardiac alpha1 increases peak current, shifts the voltage dependence of activation and accelerates activation and inactivation (PMID:7679112). The horse protein is 99.78% identical to human CACNB3 over the shared core and groups with the beta3 lineage (PTHR11824:SF8) rather than the other beta paralogs, so this beta3-specific evidence transfers. The horse gene review records the same role as calcium channel regulator activity in its core function. Horse GOA carries calcium ion transport, calcium ion transmembrane transport and channel-complex terms but no regulation-of-transport process term, so the prediction is novel for the target. It is a correct but general parent of the positive regulation of voltage-gated calcium channel activity that the evidence supports. Training-set membership is unknown.
Supporting Evidence:
file:human/CACNB3/CACNB3-uniprot.txt: "CC -!- FUNCTION: Regulatory subunit of the voltage-gated calcium channel that CC gives rise to L-type calcium currents (PubMed:8119293). Increases CC CACNA1B peak calcium current and shifts the voltage dependencies of CC channel activation and inactivation (By similarity). Increases CACNA1C CC peak calcium current and shifts the voltage dependencies of channel CC activation and inactivation (By similarity). CC {ECO:0000250|UniProtKB:P54287, ECO:0000250|UniProtKB:Q9MZL3, CC ECO:0000269|PubMed:8119293}."
file:HORSE/CACNB3/CACNB3-bioinformatics/RESULTS.md: "The horse sequence A0A5F5PZM5 (517 residues) aligns to human P54284 (484 residues) with 97.11% identity across 484 paired residues. Paired coverage is 100.0% of the human sequence and 93.62% of the horse sequence."
PMID:7679112: "Coexpression of beta 3 with a cardiac alpha 1 in Xenopus oocytes induces similar changes in Ca2+ channel activity as beta 1 and beta 2, that is, it increases peak currents, modulates the voltage dependence of activation, and accelerates activation."