{"gene":"CACNB1","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2011,"finding":"Targeted deletion of Cacnb1 (β1 subunit of DHPR) in mice caused muscle pre-patterning defects, aberrant innervation, and precocious maturation of the NMJ; reintroduction of Cacnb1 into null muscles reversed these defects. The mechanism was shown to be independent of excitation-contraction coupling but required Ca2+ influx through the L-type Ca2+ channel, demonstrating that skeletal muscle DHPR retrogradely regulates NMJ patterning and formation.","method":"Conditional knockout mice (Cacnb1−/−), rescue by reintroduction of Cacnb1, Ca2+ influx assays, genetic epistasis","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype, genetic rescue, multiple orthogonal experiments including Ca2+ influx measurements and epistasis","pmids":["21441923"],"is_preprint":false},{"year":2005,"finding":"Nonsense mutations in the zebrafish CACNB1 gene (encoding the DHPR β1 subunit) abolish DHPR expression in skeletal muscle, eliminating excitation-contraction coupling; muscles fail to contract with KCl depolarization but respond to caffeine (a ryanodine receptor agonist), placing CACNB1 upstream of ryanodine receptor activation in EC coupling.","method":"Genetic screen, immunohistochemistry, electrophysiology, caffeine stimulation assay in zebrafish relaxed mutants","journal":"Cell calcium","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function in vivo with defined molecular and functional phenotype, multiple orthogonal methods (IHC, electrophysiology, pharmacological dissection)","pmids":["16368137"],"is_preprint":false},{"year":2019,"finding":"Genetic ablation of Cacnb1 (DHPR β1 subunit) in CRD-Nrg1−/− mice (which lack Schwann cells) rescued muscle denervation and neuromuscular synapse loss, placing DHPR/Cacnb1-mediated muscle activity downstream of acetylcholine receptor signaling in a pathway that destabilizes developing NMJs; blockade of muscle activity via Cacnb1 or Ryr1 deletion was both necessary and sufficient to preserve NMJs lacking Schwann cells.","method":"Genetic epistasis (double knockout mice: CRD-Nrg1−/−Cacnb1−/−), electrophysiology","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous genetic epistasis with double KO mice, electrophysiological validation, defines pathway position","pmids":["30870432"],"is_preprint":false},{"year":2017,"finding":"A novel malignant hyperthermia-associated variant V156A in CACNB1 (β1a subunit of DHPR) was shown to reduce thermal stability of the SH3/guanylate kinase core domain of β1a, shift voltage dependence of channel activation by −2 mV, elevate resting free Ca2+ and Na+ in myotubes, and increase plasmalemmal Ca2+ entry via NCX and/or TRPC channels, without altering Ca2+ conductance, current kinetics, or SR Ca2+ load.","method":"Differential scanning fluorimetry, whole-cell patch clamp, resting ion concentration measurements, expression of variant in β1-null myotubes","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution in null myotubes, structure-function mutagenesis, multiple orthogonal methods in single study","pmids":["29212769"],"is_preprint":false},{"year":2007,"finding":"Affinity purification identified CACNB1 (β1 subunit of L-type voltage-dependent Ca2+ channels) as a direct binding protein of rapamycin analogs WYE-592 and ILS-920; electrophysiological analysis showed these compounds inhibit L-type Ca2+ channels in hippocampal neurons and DRG cells, suggesting CACNB1 mediates part of their neuroprotective activity.","method":"Affinity purification, electrophysiology (patch clamp in rat neurons)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity purification identifies binding, electrophysiology confirms functional effect, single lab with two orthogonal methods","pmids":["18162540"],"is_preprint":false},{"year":1999,"finding":"The structure of the human CACNB1 gene was determined: it spans 25 kb, contains 13 exons, and undergoes alternative splicing at exon 7 (central domain) and exon 13 (3′ domain), producing the β1a, β1b, and β1c isoforms.","method":"Genomic sequencing, comparison with cDNA sequences","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct genomic sequencing and cDNA comparison in single study; structural characterization without functional mutagenesis","pmids":["10624822"],"is_preprint":false},{"year":2022,"finding":"Cacnb1 deletion in T cells enhanced apoptosis and impaired clonal expansion after LCMV infection, but was dispensable for T cell proliferation, cytokine production, and Ca2+ signaling. Patch-clamp electrophysiology and Ca2+ recordings failed to detect voltage-gated Ca2+ currents upon depolarization in human and mouse T cells, demonstrating that CaVβ1 regulates T cell function independently of voltage-gated Ca2+ channel activity.","method":"Cacnb1 conditional knockout mice, LCMV infection model, patch clamp electrophysiology, Ca2+ recordings, flow cytometry","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with defined cellular phenotype, negative VGCC electrophysiology rigorously establishes channel-independent mechanism, multiple orthogonal methods","pmids":["35440113"],"is_preprint":false},{"year":2022,"finding":"A novel CaVβ1b variant (p.R296C) identified in an ASD patient inhibits both L-type and N-type VGCCs compared to wild-type CaVβ1b, as shown by whole-cell and single-channel patch clamp. Co-immunoprecipitation showed that interaction with and modulation by the RGK-protein Gem is intact in this variant.","method":"Whole-cell patch clamp, single-channel patch clamp, co-immunoprecipitation/Western blot","journal":"Naunyn-Schmiedeberg's archives of pharmacology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct electrophysiology with variant and Co-IP, single lab, two orthogonal methods","pmids":["35122502"],"is_preprint":false},{"year":2010,"finding":"miR-328 was shown to directly target CACNB1 (encoding the L-type Ca2+ channel β1 subunit) and CACNA1C; forced miR-328 expression reduced CACNB1 protein levels (confirmed by Western blot and luciferase reporter assay), diminished L-type Ca2+ current, and shortened atrial action potential duration, contributing to atrial fibrillation remodeling.","method":"Luciferase reporter assay, Western blot, adenoviral overexpression in canine atrium, transgenic mice, antagomiR rescue","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter directly confirms CACNB1 as miR-328 target, Western blot and electrophysiology in two models (canine and mouse), single lab","pmids":["21098446"],"is_preprint":false},{"year":2020,"finding":"miR-195 directly targets CACNB1 (encoding CaVβ1), as confirmed by luciferase assay; overexpression of miR-195 reduced CaVβ1 protein levels in cardiomyocytes and mouse hearts, contributed to arrhythmia induced by cardiac hypertrophy, and miR-195 inhibition reversed decreased cardiac function and arrhythmia in TAC mice.","method":"Luciferase reporter assay, Western blot, lentiviral overexpression/inhibition in mice and neonatal cardiomyocytes, TAC model, ECG","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase assay directly confirms CACNB1 targeting, in vivo rescue and phenotypic readout, single lab","pmids":["32468736"],"is_preprint":false},{"year":2025,"finding":"Homozygous loss-of-function variants in exon 2 of CACNB1 cause a new congenital muscular disorder (early-onset weakness, elevated CK, ptosis). CRISPR-Cas9-mediated replication of one variant (c.85-1G>A) in LHCN-M2 myotubes demonstrated loss of β1 subunit protein and severely reduced protein levels of the DHPR pore-forming α1S subunit, showing that β1 is required for α1S stability.","method":"Exome sequencing, SNP array homozygosity mapping, long-read RNA sequencing, CRISPR-Cas9 base-editing in LHCN-M2 cells, Western blot","journal":"European journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR-engineered loss-of-function cell model, protein-level validation, multiple orthogonal methods, clinically confirmed phenotype","pmids":["41023410"],"is_preprint":false},{"year":2025,"finding":"CaVβ1 isoform expression in skeletal muscle is developmentally regulated through differential promoter activation; the embryonic isoform CaVβ1A is expressed in embryonic muscle and re-expressed in denervated adult muscle after nerve injury alongside CaVβ1E. Functional analyses in aneural agrin-induced AChR clustering on primary myotubes showed these isoforms contribute to NMJ formation; their expression during early post-natal development is essential for NMJ maturation and long-term maintenance.","method":"Promoter activity assays, denervation model, aneural agrin-induced AChR clustering on primary myotubes, developmental expression profiling","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assay on primary myotubes, developmental isoform characterization, single lab with multiple approaches","pmids":["40801641"],"is_preprint":false},{"year":2025,"finding":"In a high-fat diet mouse model, PQBP1 suppression altered alternative splicing of Cacnb1; HFD-induced splicing isoforms of Cacnb1 impaired pre-synaptic vesicle release in primary neurons, and AAV-mediated restoration of wild-type Cacnb1 rescued synaptic and cognitive dysfunctions in HFD mice. Cacnb1 and CASK both regulate STXBP1 (essential for synaptic vesicle release) via direct interaction.","method":"RNA-seq, AAV gene delivery rescue, primary neuron functional assays, co-expression/interaction network analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — AAV rescue in vivo and primary neuron assays support mechanistic role; direct interaction with STXBP1 inferred from network/interaction data without explicit co-IP; preprint, single lab","pmids":["40502014"],"is_preprint":true},{"year":2025,"finding":"CACNB1 knockdown in H9c2 cardiomyocytes reduced mepivacaine- and hypoxia/reoxygenation-induced apoptosis, inflammation (TNF-α, IL-1β, IL-6), oxidative stress, and G1 arrest; mechanistically, CACNB1 knockdown enhanced Nrf2 nuclear translocation via the CACNB1/NLRP3/Nrf2 axis.","method":"siRNA knockdown in H9c2 cells, flow cytometry (apoptosis, cell cycle), ELISA (cytokines), oxidative stress markers, Nrf2 nuclear translocation assay","journal":"Molecular medicine reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single cell line, knockdown phenotype without direct biochemical reconstitution of CACNB1/NLRP3/Nrf2 interaction","pmids":["41416438"],"is_preprint":false}],"current_model":"CACNB1 encodes the β1 auxiliary subunit of the skeletal muscle dihydropyridine receptor (DHPR/CaV1), which is required for excitation-contraction coupling by coupling membrane depolarization to ryanodine receptor-mediated SR Ca2+ release, stabilizing the pore-forming α1S subunit, and retrogradely regulating neuromuscular junction patterning and formation via Ca2+ influx-dependent signaling; additionally, CaVβ1 regulates T cell survival and clonal expansion independently of voltage-gated Ca2+ channel activity, is expressed as developmentally regulated isoforms that govern NMJ maturation, and is subject to post-transcriptional repression by miR-328 and miR-195, while loss-of-function mutations cause congenital myopathy."},"narrative":{"mechanistic_narrative":"CACNB1 encodes the CaVβ1 auxiliary subunit of the skeletal muscle dihydropyridine receptor (DHPR/L-type CaV1 channel), where it is required for excitation–contraction coupling: loss-of-function abolishes DHPR expression and depolarization-evoked contraction while leaving direct ryanodine receptor activation intact, placing CaVβ1 upstream of RyR-mediated SR Ca2+ release [PMID:16368137]. CaVβ1 stabilizes the pore-forming α1S subunit, and homozygous loss-of-function variants that eliminate the β1 protein also severely deplete α1S, causing a congenital muscular disorder [PMID:41023410]. Beyond its channel role, skeletal muscle DHPR acts retrogradely to pattern the neuromuscular junction through Ca2+ influx-dependent, EC-coupling-independent signaling [PMID:21441923], and CaVβ1 deletion preserves NMJs in Schwann-cell-deficient muscle, defining muscle DHPR activity as a destabilizing signal downstream of acetylcholine receptor signaling [PMID:30870432]; developmentally regulated CaVβ1 isoforms generated by differential promoter use further govern NMJ formation and maturation [PMID:40801641]. CaVβ1 also has channel-independent functions: it sustains T cell survival and clonal expansion without any detectable voltage-gated Ca2+ current in T cells [PMID:35440113]. CACNB1 expression is repressed post-transcriptionally by miR-328 and miR-195, contributing to atrial and hypertrophic cardiac arrhythmia remodeling [PMID:21098446, PMID:32468736]. Disease-associated variants alter subunit thermal stability and resting ion handling in malignant hyperthermia [PMID:29212769] and channel inhibition in an autism context [PMID:35122502].","teleology":[{"year":2005,"claim":"Established that CACNB1 is genetically required for skeletal muscle EC coupling and acts upstream of the ryanodine receptor, resolving where the β1 subunit sits in the depolarization-to-Ca2+-release cascade.","evidence":"Nonsense mutations in zebrafish relaxed mutants with IHC, electrophysiology, and caffeine (RyR agonist) rescue","pmids":["16368137"],"confidence":"High","gaps":["Does not define the molecular interaction surface between β1 and α1S or RyR1","Zebrafish model; mammalian EC-coupling specifics not addressed"]},{"year":2007,"claim":"Identified CACNB1 as a direct binding target of neuroprotective rapamycin analogs that inhibit neuronal L-type channels, extending β1 relevance beyond muscle to neuronal channel pharmacology.","evidence":"Affinity purification and patch clamp in rat hippocampal and DRG neurons","pmids":["18162540"],"confidence":"Medium","gaps":["Binding site on CACNB1 not mapped","Causal link between β1 binding and neuroprotection not directly tested"]},{"year":2011,"claim":"Revealed a non-canonical, EC-coupling-independent role: muscle DHPR retrogradely patterns the NMJ via L-type Ca2+ influx, separating CaVβ1's signaling function from its contractile function.","evidence":"Cacnb1 knockout mice with rescue by reintroduction, Ca2+ influx assays, and genetic epistasis","pmids":["21441923"],"confidence":"High","gaps":["Downstream Ca2+-dependent effectors of retrograde signaling not identified","Molecular target of the retrograde signal at the nerve terminal unknown"]},{"year":2019,"claim":"Positioned Cacnb1-dependent muscle activity within NMJ-stabilization circuitry, showing it destabilizes developing synapses downstream of AChR signaling and that its removal preserves Schwann-cell-deficient NMJs.","evidence":"Genetic epistasis with CRD-Nrg1−/−Cacnb1−/− double knockout mice and electrophysiology","pmids":["30870432"],"confidence":"High","gaps":["Molecular mediators linking muscle activity to synapse destabilization not defined","Relationship to retrograde patterning pathway not integrated"]},{"year":2010,"claim":"Demonstrated post-transcriptional control of CACNB1 by miR-328, linking β1 downregulation to reduced L-type current and atrial fibrillation remodeling.","evidence":"Luciferase reporter, Western blot, adenoviral overexpression in canine atrium, transgenic mice, antagomiR rescue","pmids":["21098446"],"confidence":"Medium","gaps":["Relative contribution of CACNB1 vs co-target CACNA1C to phenotype not separated"]},{"year":2017,"claim":"Provided structure-function insight into a malignant hyperthermia variant, showing V156A destabilizes the SH3/guanylate kinase core and dysregulates resting ion homeostasis without changing Ca2+ conductance.","evidence":"Differential scanning fluorimetry, patch clamp, and resting ion measurements in β1-null myotubes expressing the variant","pmids":["29212769"],"confidence":"High","gaps":["Mechanism linking domain destabilization to NCX/TRPC-mediated Ca2+/Na+ entry not resolved","In vivo MH susceptibility not tested"]},{"year":2020,"claim":"Identified a second microRNA, miR-195, that directly represses CACNB1, contributing to hypertrophy-induced arrhythmia.","evidence":"Luciferase assay, Western blot, lentiviral overexpression/inhibition in mice and cardiomyocytes, TAC model, ECG","pmids":["32468736"],"confidence":"Medium","gaps":["Whether CACNB1 repression alone accounts for the arrhythmia phenotype not isolated"]},{"year":2022,"claim":"Established a channel-independent function of CaVβ1 in adaptive immunity, where it supports T cell survival and clonal expansion despite the absence of voltage-gated Ca2+ currents in T cells.","evidence":"Cacnb1 conditional knockout, LCMV infection, patch clamp, Ca2+ recordings, and flow cytometry","pmids":["35440113"],"confidence":"High","gaps":["Molecular effectors of the channel-independent survival function not identified","Subcellular partners of CaVβ1 in T cells unknown"]},{"year":2022,"claim":"Characterized an ASD-associated CaVβ1b variant (R296C) that inhibits L- and N-type channels while retaining intact RGK-protein Gem modulation, refining genotype-function relationships.","evidence":"Whole-cell and single-channel patch clamp and co-immunoprecipitation","pmids":["35122502"],"confidence":"Medium","gaps":["Causal contribution to ASD phenotype not established","Neuronal cell-type context of the variant effect untested"]},{"year":2025,"claim":"Defined CACNB1 as a congenital myopathy gene and established mechanistically that β1 is required for stability of the DHPR pore-forming α1S subunit.","evidence":"Exome sequencing, homozygosity mapping, long-read RNA-seq, CRISPR-Cas9 base-edited LHCN-M2 myotubes, Western blot","pmids":["41023410"],"confidence":"High","gaps":["Structural basis of β1-mediated α1S stabilization not resolved","Range of allelic phenotypes not fully mapped"]},{"year":2025,"claim":"Connected developmentally regulated CaVβ1 isoform expression, driven by differential promoter activation and re-induced after denervation, to NMJ formation, maturation, and maintenance.","evidence":"Promoter activity assays, denervation model, aneural agrin-induced AChR clustering on primary myotubes, developmental profiling","pmids":["40801641"],"confidence":"Medium","gaps":["Distinct molecular activities of individual isoforms not separated","Mechanism coupling isoform identity to NMJ outcome unclear"]},{"year":2025,"claim":"Implicated Cacnb1 alternative splicing in neuronal synaptic vesicle release, with diet-induced isoforms impairing presynaptic function reversible by wild-type restoration.","evidence":"RNA-seq, AAV rescue in HFD mice, primary neuron functional assays, and interaction-network analysis (preprint)","pmids":["40502014"],"confidence":"Medium","gaps":["Direct CACNB1–STXBP1 interaction inferred from network data without co-IP","Preprint; not independently confirmed"]},{"year":2025,"claim":"Proposed a CACNB1/NLRP3/Nrf2 axis whereby CACNB1 knockdown limits cardiomyocyte apoptosis, inflammation, and oxidative stress.","evidence":"siRNA knockdown in H9c2 cells with flow cytometry, ELISA, oxidative stress markers, and Nrf2 translocation assay","pmids":["41416438"],"confidence":"Low","gaps":["No direct biochemical reconstitution of the CACNB1/NLRP3/Nrf2 interactions","Single cell line, single lab","In vivo relevance untested"]},{"year":null,"claim":"The molecular basis of CaVβ1's channel-independent functions—its direct binding partners and effectors in T cells and neurons—remains undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model for β1–α1S stabilization","Effectors of retrograde NMJ signaling unidentified","Channel-independent interactome uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,3,7,10]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,3]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[1,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,2,11]}],"complexes":["DHPR/CaV1 (L-type voltage-gated Ca2+ channel)"],"partners":["CACNA1S","GEM","STXBP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q02641","full_name":"Voltage-dependent L-type calcium channel subunit beta-1","aliases":["Calcium channel voltage-dependent subunit beta 1"],"length_aa":598,"mass_kda":65.7,"function":"Regulatory subunit of L-type calcium channels (PubMed:1309651, PubMed:15615847, PubMed:8107964). Regulates the activity of L-type calcium channels that contain CACNA1A as pore-forming subunit (By similarity). Regulates the activity of L-type calcium channels that contain CACNA1C as pore-forming subunit and increases the presence of the channel complex at the cell membrane (PubMed:15615847). Required for functional expression L-type calcium channels that contain CACNA1D as pore-forming subunit (PubMed:1309651). Regulates the activity of L-type calcium channels that contain CACNA1B as pore-forming subunit (PubMed:8107964)","subcellular_location":"Cell membrane, sarcolemma; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q02641/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CACNB1","classification":"Not Classified","n_dependent_lines":26,"n_total_lines":1208,"dependency_fraction":0.02152317880794702},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CACNB1","total_profiled":1310},"omim":[{"mim_id":"606900","title":"CALCIUM CHANNEL, VOLTAGE-DEPENDENT, GAMMA-8 SUBUNIT; CACNG8","url":"https://www.omim.org/entry/606900"},{"mim_id":"606899","title":"CALCIUM CHANNEL, VOLTAGE-DEPENDENT, GAMMA-7 SUBUNIT; CACNG7","url":"https://www.omim.org/entry/606899"},{"mim_id":"606898","title":"CALCIUM CHANNEL, VOLTAGE-DEPENDENT, GAMMA-6 SUBUNIT; CACNG6","url":"https://www.omim.org/entry/606898"},{"mim_id":"606405","title":"CALCIUM CHANNEL, VOLTAGE-DEPENDENT, GAMMA-5 SUBUNIT; CACNG5","url":"https://www.omim.org/entry/606405"},{"mim_id":"606404","title":"CALCIUM CHANNEL, VOLTAGE-DEPENDENT, GAMMA-4 SUBUNIT; CACNG4","url":"https://www.omim.org/entry/606404"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":314.2},{"tissue":"tongue","ntpm":206.3}],"url":"https://www.proteinatlas.org/search/CACNB1"},"hgnc":{"alias_symbol":[],"prev_symbol":["CACNLB1"]},"alphafold":{"accession":"Q02641","domains":[{"cath_id":"2.30.30.40","chopping":"77-180","consensus_level":"high","plddt":93.8872,"start":77,"end":180},{"cath_id":"3.40.50.300","chopping":"230-285_298-413","consensus_level":"high","plddt":94.843,"start":230,"end":413}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q02641","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q02641-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q02641-F1-predicted_aligned_error_v6.png","plddt_mean":69.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CACNB1","jax_strain_url":"https://www.jax.org/strain/search?query=CACNB1"},"sequence":{"accession":"Q02641","fasta_url":"https://rest.uniprot.org/uniprotkb/Q02641.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q02641/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q02641"}},"corpus_meta":[{"pmid":"21098446","id":"PMC_21098446","title":"MicroRNA-328 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\"finding\": \"Targeted deletion of Cacnb1 (β1 subunit of DHPR) in mice caused muscle pre-patterning defects, aberrant innervation, and precocious maturation of the NMJ; reintroduction of Cacnb1 into null muscles reversed these defects. The mechanism was shown to be independent of excitation-contraction coupling but required Ca2+ influx through the L-type Ca2+ channel, demonstrating that skeletal muscle DHPR retrogradely regulates NMJ patterning and formation.\",\n      \"method\": \"Conditional knockout mice (Cacnb1−/−), rescue by reintroduction of Cacnb1, Ca2+ influx assays, genetic epistasis\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype, genetic rescue, multiple orthogonal experiments including Ca2+ influx measurements and epistasis\",\n      \"pmids\": [\"21441923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Nonsense mutations in the zebrafish CACNB1 gene (encoding the DHPR β1 subunit) abolish DHPR expression in skeletal muscle, eliminating excitation-contraction coupling; muscles fail to contract with KCl depolarization but respond to caffeine (a ryanodine receptor agonist), placing CACNB1 upstream of ryanodine receptor activation in EC coupling.\",\n      \"method\": \"Genetic screen, immunohistochemistry, electrophysiology, caffeine stimulation assay in zebrafish relaxed mutants\",\n      \"journal\": \"Cell calcium\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function in vivo with defined molecular and functional phenotype, multiple orthogonal methods (IHC, electrophysiology, pharmacological dissection)\",\n      \"pmids\": [\"16368137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Genetic ablation of Cacnb1 (DHPR β1 subunit) in CRD-Nrg1−/− mice (which lack Schwann cells) rescued muscle denervation and neuromuscular synapse loss, placing DHPR/Cacnb1-mediated muscle activity downstream of acetylcholine receptor signaling in a pathway that destabilizes developing NMJs; blockade of muscle activity via Cacnb1 or Ryr1 deletion was both necessary and sufficient to preserve NMJs lacking Schwann cells.\",\n      \"method\": \"Genetic epistasis (double knockout mice: CRD-Nrg1−/−Cacnb1−/−), electrophysiology\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous genetic epistasis with double KO mice, electrophysiological validation, defines pathway position\",\n      \"pmids\": [\"30870432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A novel malignant hyperthermia-associated variant V156A in CACNB1 (β1a subunit of DHPR) was shown to reduce thermal stability of the SH3/guanylate kinase core domain of β1a, shift voltage dependence of channel activation by −2 mV, elevate resting free Ca2+ and Na+ in myotubes, and increase plasmalemmal Ca2+ entry via NCX and/or TRPC channels, without altering Ca2+ conductance, current kinetics, or SR Ca2+ load.\",\n      \"method\": \"Differential scanning fluorimetry, whole-cell patch clamp, resting ion concentration measurements, expression of variant in β1-null myotubes\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution in null myotubes, structure-function mutagenesis, multiple orthogonal methods in single study\",\n      \"pmids\": [\"29212769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Affinity purification identified CACNB1 (β1 subunit of L-type voltage-dependent Ca2+ channels) as a direct binding protein of rapamycin analogs WYE-592 and ILS-920; electrophysiological analysis showed these compounds inhibit L-type Ca2+ channels in hippocampal neurons and DRG cells, suggesting CACNB1 mediates part of their neuroprotective activity.\",\n      \"method\": \"Affinity purification, electrophysiology (patch clamp in rat neurons)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity purification identifies binding, electrophysiology confirms functional effect, single lab with two orthogonal methods\",\n      \"pmids\": [\"18162540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The structure of the human CACNB1 gene was determined: it spans 25 kb, contains 13 exons, and undergoes alternative splicing at exon 7 (central domain) and exon 13 (3′ domain), producing the β1a, β1b, and β1c isoforms.\",\n      \"method\": \"Genomic sequencing, comparison with cDNA sequences\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct genomic sequencing and cDNA comparison in single study; structural characterization without functional mutagenesis\",\n      \"pmids\": [\"10624822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cacnb1 deletion in T cells enhanced apoptosis and impaired clonal expansion after LCMV infection, but was dispensable for T cell proliferation, cytokine production, and Ca2+ signaling. Patch-clamp electrophysiology and Ca2+ recordings failed to detect voltage-gated Ca2+ currents upon depolarization in human and mouse T cells, demonstrating that CaVβ1 regulates T cell function independently of voltage-gated Ca2+ channel activity.\",\n      \"method\": \"Cacnb1 conditional knockout mice, LCMV infection model, patch clamp electrophysiology, Ca2+ recordings, flow cytometry\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with defined cellular phenotype, negative VGCC electrophysiology rigorously establishes channel-independent mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"35440113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A novel CaVβ1b variant (p.R296C) identified in an ASD patient inhibits both L-type and N-type VGCCs compared to wild-type CaVβ1b, as shown by whole-cell and single-channel patch clamp. Co-immunoprecipitation showed that interaction with and modulation by the RGK-protein Gem is intact in this variant.\",\n      \"method\": \"Whole-cell patch clamp, single-channel patch clamp, co-immunoprecipitation/Western blot\",\n      \"journal\": \"Naunyn-Schmiedeberg's archives of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct electrophysiology with variant and Co-IP, single lab, two orthogonal methods\",\n      \"pmids\": [\"35122502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"miR-328 was shown to directly target CACNB1 (encoding the L-type Ca2+ channel β1 subunit) and CACNA1C; forced miR-328 expression reduced CACNB1 protein levels (confirmed by Western blot and luciferase reporter assay), diminished L-type Ca2+ current, and shortened atrial action potential duration, contributing to atrial fibrillation remodeling.\",\n      \"method\": \"Luciferase reporter assay, Western blot, adenoviral overexpression in canine atrium, transgenic mice, antagomiR rescue\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter directly confirms CACNB1 as miR-328 target, Western blot and electrophysiology in two models (canine and mouse), single lab\",\n      \"pmids\": [\"21098446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-195 directly targets CACNB1 (encoding CaVβ1), as confirmed by luciferase assay; overexpression of miR-195 reduced CaVβ1 protein levels in cardiomyocytes and mouse hearts, contributed to arrhythmia induced by cardiac hypertrophy, and miR-195 inhibition reversed decreased cardiac function and arrhythmia in TAC mice.\",\n      \"method\": \"Luciferase reporter assay, Western blot, lentiviral overexpression/inhibition in mice and neonatal cardiomyocytes, TAC model, ECG\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase assay directly confirms CACNB1 targeting, in vivo rescue and phenotypic readout, single lab\",\n      \"pmids\": [\"32468736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Homozygous loss-of-function variants in exon 2 of CACNB1 cause a new congenital muscular disorder (early-onset weakness, elevated CK, ptosis). CRISPR-Cas9-mediated replication of one variant (c.85-1G>A) in LHCN-M2 myotubes demonstrated loss of β1 subunit protein and severely reduced protein levels of the DHPR pore-forming α1S subunit, showing that β1 is required for α1S stability.\",\n      \"method\": \"Exome sequencing, SNP array homozygosity mapping, long-read RNA sequencing, CRISPR-Cas9 base-editing in LHCN-M2 cells, Western blot\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR-engineered loss-of-function cell model, protein-level validation, multiple orthogonal methods, clinically confirmed phenotype\",\n      \"pmids\": [\"41023410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CaVβ1 isoform expression in skeletal muscle is developmentally regulated through differential promoter activation; the embryonic isoform CaVβ1A is expressed in embryonic muscle and re-expressed in denervated adult muscle after nerve injury alongside CaVβ1E. Functional analyses in aneural agrin-induced AChR clustering on primary myotubes showed these isoforms contribute to NMJ formation; their expression during early post-natal development is essential for NMJ maturation and long-term maintenance.\",\n      \"method\": \"Promoter activity assays, denervation model, aneural agrin-induced AChR clustering on primary myotubes, developmental expression profiling\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assay on primary myotubes, developmental isoform characterization, single lab with multiple approaches\",\n      \"pmids\": [\"40801641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a high-fat diet mouse model, PQBP1 suppression altered alternative splicing of Cacnb1; HFD-induced splicing isoforms of Cacnb1 impaired pre-synaptic vesicle release in primary neurons, and AAV-mediated restoration of wild-type Cacnb1 rescued synaptic and cognitive dysfunctions in HFD mice. Cacnb1 and CASK both regulate STXBP1 (essential for synaptic vesicle release) via direct interaction.\",\n      \"method\": \"RNA-seq, AAV gene delivery rescue, primary neuron functional assays, co-expression/interaction network analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — AAV rescue in vivo and primary neuron assays support mechanistic role; direct interaction with STXBP1 inferred from network/interaction data without explicit co-IP; preprint, single lab\",\n      \"pmids\": [\"40502014\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CACNB1 knockdown in H9c2 cardiomyocytes reduced mepivacaine- and hypoxia/reoxygenation-induced apoptosis, inflammation (TNF-α, IL-1β, IL-6), oxidative stress, and G1 arrest; mechanistically, CACNB1 knockdown enhanced Nrf2 nuclear translocation via the CACNB1/NLRP3/Nrf2 axis.\",\n      \"method\": \"siRNA knockdown in H9c2 cells, flow cytometry (apoptosis, cell cycle), ELISA (cytokines), oxidative stress markers, Nrf2 nuclear translocation assay\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single cell line, knockdown phenotype without direct biochemical reconstitution of CACNB1/NLRP3/Nrf2 interaction\",\n      \"pmids\": [\"41416438\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CACNB1 encodes the β1 auxiliary subunit of the skeletal muscle dihydropyridine receptor (DHPR/CaV1), which is required for excitation-contraction coupling by coupling membrane depolarization to ryanodine receptor-mediated SR Ca2+ release, stabilizing the pore-forming α1S subunit, and retrogradely regulating neuromuscular junction patterning and formation via Ca2+ influx-dependent signaling; additionally, CaVβ1 regulates T cell survival and clonal expansion independently of voltage-gated Ca2+ channel activity, is expressed as developmentally regulated isoforms that govern NMJ maturation, and is subject to post-transcriptional repression by miR-328 and miR-195, while loss-of-function mutations cause congenital myopathy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CACNB1 encodes the CaVβ1 auxiliary subunit of the skeletal muscle dihydropyridine receptor (DHPR/L-type CaV1 channel), where it is required for excitation–contraction coupling: loss-of-function abolishes DHPR expression and depolarization-evoked contraction while leaving direct ryanodine receptor activation intact, placing CaVβ1 upstream of RyR-mediated SR Ca2+ release [#1]. CaVβ1 stabilizes the pore-forming α1S subunit, and homozygous loss-of-function variants that eliminate the β1 protein also severely deplete α1S, causing a congenital muscular disorder [#10]. Beyond its channel role, skeletal muscle DHPR acts retrogradely to pattern the neuromuscular junction through Ca2+ influx-dependent, EC-coupling-independent signaling [#0], and CaVβ1 deletion preserves NMJs in Schwann-cell-deficient muscle, defining muscle DHPR activity as a destabilizing signal downstream of acetylcholine receptor signaling [#2]; developmentally regulated CaVβ1 isoforms generated by differential promoter use further govern NMJ formation and maturation [#11]. CaVβ1 also has channel-independent functions: it sustains T cell survival and clonal expansion without any detectable voltage-gated Ca2+ current in T cells [#6]. CACNB1 expression is repressed post-transcriptionally by miR-328 and miR-195, contributing to atrial and hypertrophic cardiac arrhythmia remodeling [#8, #9]. Disease-associated variants alter subunit thermal stability and resting ion handling in malignant hyperthermia [#3] and channel inhibition in an autism context [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that CACNB1 is genetically required for skeletal muscle EC coupling and acts upstream of the ryanodine receptor, resolving where the β1 subunit sits in the depolarization-to-Ca2+-release cascade.\",\n      \"evidence\": \"Nonsense mutations in zebrafish relaxed mutants with IHC, electrophysiology, and caffeine (RyR agonist) rescue\",\n      \"pmids\": [\"16368137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the molecular interaction surface between β1 and α1S or RyR1\", \"Zebrafish model; mammalian EC-coupling specifics not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified CACNB1 as a direct binding target of neuroprotective rapamycin analogs that inhibit neuronal L-type channels, extending β1 relevance beyond muscle to neuronal channel pharmacology.\",\n      \"evidence\": \"Affinity purification and patch clamp in rat hippocampal and DRG neurons\",\n      \"pmids\": [\"18162540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding site on CACNB1 not mapped\", \"Causal link between β1 binding and neuroprotection not directly tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed a non-canonical, EC-coupling-independent role: muscle DHPR retrogradely patterns the NMJ via L-type Ca2+ influx, separating CaVβ1's signaling function from its contractile function.\",\n      \"evidence\": \"Cacnb1 knockout mice with rescue by reintroduction, Ca2+ influx assays, and genetic epistasis\",\n      \"pmids\": [\"21441923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream Ca2+-dependent effectors of retrograde signaling not identified\", \"Molecular target of the retrograde signal at the nerve terminal unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Positioned Cacnb1-dependent muscle activity within NMJ-stabilization circuitry, showing it destabilizes developing synapses downstream of AChR signaling and that its removal preserves Schwann-cell-deficient NMJs.\",\n      \"evidence\": \"Genetic epistasis with CRD-Nrg1−/−Cacnb1−/− double knockout mice and electrophysiology\",\n      \"pmids\": [\"30870432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mediators linking muscle activity to synapse destabilization not defined\", \"Relationship to retrograde patterning pathway not integrated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated post-transcriptional control of CACNB1 by miR-328, linking β1 downregulation to reduced L-type current and atrial fibrillation remodeling.\",\n      \"evidence\": \"Luciferase reporter, Western blot, adenoviral overexpression in canine atrium, transgenic mice, antagomiR rescue\",\n      \"pmids\": [\"21098446\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of CACNB1 vs co-target CACNA1C to phenotype not separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided structure-function insight into a malignant hyperthermia variant, showing V156A destabilizes the SH3/guanylate kinase core and dysregulates resting ion homeostasis without changing Ca2+ conductance.\",\n      \"evidence\": \"Differential scanning fluorimetry, patch clamp, and resting ion measurements in β1-null myotubes expressing the variant\",\n      \"pmids\": [\"29212769\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking domain destabilization to NCX/TRPC-mediated Ca2+/Na+ entry not resolved\", \"In vivo MH susceptibility not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a second microRNA, miR-195, that directly represses CACNB1, contributing to hypertrophy-induced arrhythmia.\",\n      \"evidence\": \"Luciferase assay, Western blot, lentiviral overexpression/inhibition in mice and cardiomyocytes, TAC model, ECG\",\n      \"pmids\": [\"32468736\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CACNB1 repression alone accounts for the arrhythmia phenotype not isolated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a channel-independent function of CaVβ1 in adaptive immunity, where it supports T cell survival and clonal expansion despite the absence of voltage-gated Ca2+ currents in T cells.\",\n      \"evidence\": \"Cacnb1 conditional knockout, LCMV infection, patch clamp, Ca2+ recordings, and flow cytometry\",\n      \"pmids\": [\"35440113\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular effectors of the channel-independent survival function not identified\", \"Subcellular partners of CaVβ1 in T cells unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Characterized an ASD-associated CaVβ1b variant (R296C) that inhibits L- and N-type channels while retaining intact RGK-protein Gem modulation, refining genotype-function relationships.\",\n      \"evidence\": \"Whole-cell and single-channel patch clamp and co-immunoprecipitation\",\n      \"pmids\": [\"35122502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal contribution to ASD phenotype not established\", \"Neuronal cell-type context of the variant effect untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined CACNB1 as a congenital myopathy gene and established mechanistically that β1 is required for stability of the DHPR pore-forming α1S subunit.\",\n      \"evidence\": \"Exome sequencing, homozygosity mapping, long-read RNA-seq, CRISPR-Cas9 base-edited LHCN-M2 myotubes, Western blot\",\n      \"pmids\": [\"41023410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of β1-mediated α1S stabilization not resolved\", \"Range of allelic phenotypes not fully mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected developmentally regulated CaVβ1 isoform expression, driven by differential promoter activation and re-induced after denervation, to NMJ formation, maturation, and maintenance.\",\n      \"evidence\": \"Promoter activity assays, denervation model, aneural agrin-induced AChR clustering on primary myotubes, developmental profiling\",\n      \"pmids\": [\"40801641\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Distinct molecular activities of individual isoforms not separated\", \"Mechanism coupling isoform identity to NMJ outcome unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated Cacnb1 alternative splicing in neuronal synaptic vesicle release, with diet-induced isoforms impairing presynaptic function reversible by wild-type restoration.\",\n      \"evidence\": \"RNA-seq, AAV rescue in HFD mice, primary neuron functional assays, and interaction-network analysis (preprint)\",\n      \"pmids\": [\"40502014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CACNB1–STXBP1 interaction inferred from network data without co-IP\", \"Preprint; not independently confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed a CACNB1/NLRP3/Nrf2 axis whereby CACNB1 knockdown limits cardiomyocyte apoptosis, inflammation, and oxidative stress.\",\n      \"evidence\": \"siRNA knockdown in H9c2 cells with flow cytometry, ELISA, oxidative stress markers, and Nrf2 translocation assay\",\n      \"pmids\": [\"41416438\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct biochemical reconstitution of the CACNB1/NLRP3/Nrf2 interactions\", \"Single cell line, single lab\", \"In vivo relevance untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular basis of CaVβ1's channel-independent functions—its direct binding partners and effectors in T cells and neurons—remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model for β1–α1S stabilization\", \"Effectors of retrograde NMJ signaling unidentified\", \"Channel-independent interactome uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 3, 7, 10]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [1, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 2, 11]}\n    ],\n    \"complexes\": [\"DHPR/CaV1 (L-type voltage-gated Ca2+ channel)\"],\n    \"partners\": [\"CACNA1S\", \"Gem\", \"STXBP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}