Affinage

CACNB1

Voltage-dependent L-type calcium channel subunit beta-1 · UniProt Q02641

Length
598 aa
Mass
65.7 kDa
Annotated
2026-06-09
46 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2005 High

    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

    PMID:16368137

    Open questions at the time
    • Does not define the molecular interaction surface between β1 and α1S or RyR1
    • Zebrafish model; mammalian EC-coupling specifics not addressed
  2. 2007 Medium

    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

    PMID:18162540

    Open questions at the time
    • Binding site on CACNB1 not mapped
    • Causal link between β1 binding and neuroprotection not directly tested
  3. 2011 High

    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

    PMID:21441923

    Open questions at the time
    • Downstream Ca2+-dependent effectors of retrograde signaling not identified
    • Molecular target of the retrograde signal at the nerve terminal unknown
  4. 2019 High

    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

    PMID:30870432

    Open questions at the time
    • Molecular mediators linking muscle activity to synapse destabilization not defined
    • Relationship to retrograde patterning pathway not integrated
  5. 2010 Medium

    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

    PMID:21098446

    Open questions at the time
    • Relative contribution of CACNB1 vs co-target CACNA1C to phenotype not separated
  6. 2017 High

    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

    PMID:29212769

    Open questions at the time
    • Mechanism linking domain destabilization to NCX/TRPC-mediated Ca2+/Na+ entry not resolved
    • In vivo MH susceptibility not tested
  7. 2020 Medium

    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

    PMID:32468736

    Open questions at the time
    • Whether CACNB1 repression alone accounts for the arrhythmia phenotype not isolated
  8. 2022 High

    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

    PMID:35440113

    Open questions at the time
    • Molecular effectors of the channel-independent survival function not identified
    • Subcellular partners of CaVβ1 in T cells unknown
  9. 2022 Medium

    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

    PMID:35122502

    Open questions at the time
    • Causal contribution to ASD phenotype not established
    • Neuronal cell-type context of the variant effect untested
  10. 2025 High

    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

    PMID:41023410

    Open questions at the time
    • Structural basis of β1-mediated α1S stabilization not resolved
    • Range of allelic phenotypes not fully mapped
  11. 2025 Medium

    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

    PMID:40801641

    Open questions at the time
    • Distinct molecular activities of individual isoforms not separated
    • Mechanism coupling isoform identity to NMJ outcome unclear
  12. 2025 Medium

    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)

    PMID:40502014

    Open questions at the time
    • Direct CACNB1–STXBP1 interaction inferred from network data without co-IP
    • Preprint; not independently confirmed
  13. 2025 Low

    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

    PMID:41416438

    Open questions at the time
    • No direct biochemical reconstitution of the CACNB1/NLRP3/Nrf2 interactions
    • Single cell line, single lab
    • In vivo relevance untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular basis of CaVβ1's channel-independent functions—its direct binding partners and effectors in T cells and neurons—remains undefined.
  • No structural model for β1–α1S stabilization
  • Effectors of retrograde NMJ signaling unidentified
  • Channel-independent interactome uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 2 R-HSA-397014 Muscle contraction 2 R-HSA-168256 Immune System 1
Partners
CACNA1SGEMSTXBP1
Complex memberships
DHPR/CaV1 (L-type voltage-gated Ca2+ channel)

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 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. Conditional knockout mice (Cacnb1−/−), rescue by reintroduction of Cacnb1, Ca2+ influx assays, genetic epistasis Nature neuroscience High 21441923
2005 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. Genetic screen, immunohistochemistry, electrophysiology, caffeine stimulation assay in zebrafish relaxed mutants Cell calcium High 16368137
2019 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. Genetic epistasis (double knockout mice: CRD-Nrg1−/−Cacnb1−/−), electrophysiology PLoS genetics High 30870432
2017 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. Differential scanning fluorimetry, whole-cell patch clamp, resting ion concentration measurements, expression of variant in β1-null myotubes American journal of physiology. Cell physiology High 29212769
2007 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. Affinity purification, electrophysiology (patch clamp in rat neurons) Proceedings of the National Academy of Sciences of the United States of America Medium 18162540
1999 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. Genomic sequencing, comparison with cDNA sequences Neuroscience letters Medium 10624822
2022 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. Cacnb1 conditional knockout mice, LCMV infection model, patch clamp electrophysiology, Ca2+ recordings, flow cytometry Nature communications High 35440113
2022 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. Whole-cell patch clamp, single-channel patch clamp, co-immunoprecipitation/Western blot Naunyn-Schmiedeberg's archives of pharmacology Medium 35122502
2010 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. Luciferase reporter assay, Western blot, adenoviral overexpression in canine atrium, transgenic mice, antagomiR rescue Circulation Medium 21098446
2020 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. Luciferase reporter assay, Western blot, lentiviral overexpression/inhibition in mice and neonatal cardiomyocytes, TAC model, ECG Journal of cellular and molecular medicine Medium 32468736
2025 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. Exome sequencing, SNP array homozygosity mapping, long-read RNA sequencing, CRISPR-Cas9 base-editing in LHCN-M2 cells, Western blot European journal of human genetics High 41023410
2025 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. Promoter activity assays, denervation model, aneural agrin-induced AChR clustering on primary myotubes, developmental expression profiling Cells Medium 40801641
2025 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. RNA-seq, AAV gene delivery rescue, primary neuron functional assays, co-expression/interaction network analysis bioRxivpreprint Medium 40502014
2025 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. siRNA knockdown in H9c2 cells, flow cytometry (apoptosis, cell cycle), ELISA (cytokines), oxidative stress markers, Nrf2 nuclear translocation assay Molecular medicine reports Low 41416438

Source papers

Stage 0 corpus · 46 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 MicroRNA-328 contributes to adverse electrical remodeling in atrial fibrillation. Circulation 372 21098446
2020 Genome-wide detection of tandem DNA repeats that are expanded in autism. Nature 168 32717741
2007 Binding of rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities. Proceedings of the National Academy of Sciences of the United States of America 95 18162540
2003 Identification and characterization of LASP2 gene in silico. International journal of molecular medicine 83 12883659
2016 Sexual divergence in microtubule function: the novel intranasal microtubule targeting SKIP normalizes axonal transport and enhances memory. Molecular psychiatry 76 26782054
2011 Neuromuscular synaptic patterning requires the function of skeletal muscle dihydropyridine receptors. Nature neuroscience 58 21441923
2022 Circulating microRNAs predispose to takotsubo syndrome following high-dose adrenaline exposure. Cardiovascular research 44 34155498
2017 Profiling of Circulating Serum MicroRNAs in Children with Autism Spectrum Disorder using Stem-loop qRT-PCR Assay. Folia medica 41 28384108
2005 Non-sense mutations in the dihydropyridine receptor beta1 gene, CACNB1, paralyze zebrafish relaxed mutants. Cell calcium 36 16368137
1993 Exclusion of malignant hyperthermia susceptibility (MHS) from a putative MHS2 locus on chromosome 17q and of the alpha 1, beta 1, and gamma subunits of the dihydropyridine receptor calcium channel as candidates for the molecular defect. Human molecular genetics 35 8395939
1993 Genetic mapping of the beta 1- and gamma-subunits of the human skeletal muscle L-type voltage-dependent calcium channel on chromosome 17q and exclusion as candidate genes for malignant hyperthermia susceptibility. Human molecular genetics 35 8395940
2022 Cavβ1 regulates T cell expansion and apoptosis independently of voltage-gated Ca2+ channel function. Nature communications 32 35440113
2021 A genome-wide scan to identify signatures of selection in two Iranian indigenous chicken ecotypes. Genetics, selection, evolution : GSE 32 34503452
2012 Antidepressant-dependent mRNA changes in mouse associated with hippocampal neurogenesis in a mouse model of depression. Pharmacogenetics and genomics 29 23026812
1997 Searching for migraine genes: exclusion of 290 cM out of the whole human genome. Italian journal of neurological sciences 28 9412851
2012 Confirmation of an epilepsy modifier locus on mouse chromosome 11 and candidate gene analysis by RNA-Seq. Genes, brain, and behavior 23 22471526
1993 Assignment of the human gene for the beta subunit of the voltage-dependent calcium channel (CACNLB1) to chromosome 17 using somatic cell hybrids and linkage mapping. Genomics 23 8381767
2019 Proestrus Differentially Regulates Expression of Ion Channel and Calcium Homeostasis Genes in GnRH Neurons of Mice. Frontiers in molecular neuroscience 21 31213979
2020 Up-regulation of miR-195 contributes to cardiac hypertrophy-induced arrhythmia by targeting calcium and potassium channels. Journal of cellular and molecular medicine 19 32468736
2019 Conversion of human cardiac progenitor cells into cardiac pacemaker-like cells. Journal of molecular and cellular cardiology 19 31678351
2012 Shortening and intracellular Ca2+ in ventricular myocytes and expression of genes encoding cardiac muscle proteins in early onset type 2 diabetic Goto-Kakizaki rats. Experimental physiology 16 22581745
2019 Blocking skeletal muscle DHPRs/Ryr1 prevents neuromuscular synapse loss in mutant mice deficient in type III Neuregulin 1 (CRD-Nrg1). PLoS genetics 15 30870432
2004 Identification and characterization of human ARHGAP23 gene in silico. International journal of oncology 15 15254754
2018 Cross-Database Analysis Reveals Sensitive Biomarkers for Combined Therapy for ERBB2+ Gastric Cancer. Frontiers in pharmacology 14 30123134
2016 Sequencing of genes involved in the movement of calcium across human skeletal muscle sarcoplasmic reticulum: continuing the search for genes associated with malignant hyperthermia. Anaesthesia and intensive care 13 27832566
2017 Screening and validation of differentially expressed extracellular miRNAs in acute pancreatitis. Molecular medicine reports 12 28849189
1999 Structure and alternative splicing of the gene encoding the human beta1 subunit of voltage dependent calcium channels. Neuroscience letters 11 10624822
2024 Exploring variances in meat quality between Qingyuan partridge chicken and Cobb broiler: Insights from combined multi-omics analysis. Poultry science 10 39721276
2022 Development and Validation of an 8-Gene Signature to Improve Survival Prediction of Colorectal Cancer. Frontiers in oncology 10 35619909
2019 The influence of Ca2+ concentration on voltage-dependent L-type calcium channels' expression in the marbled eel (Anguilla marmorata). Gene 9 31479714
2017 Functional and structural characterization of a novel malignant hyperthermia-susceptible variant of DHPR-β1a subunit (CACNB1). American journal of physiology. Cell physiology 9 29212769
2019 Increased calcium channel in the lamina propria of aging rat. Aging 7 31682233
2022 Inhibitory effects on L- and N-type calcium channels by a novel CaVβ1 variant identified in a patient with autism spectrum disorder. Naunyn-Schmiedeberg's archives of pharmacology 6 35122502
2022 The SLC27A1 Gene and Its Enriched PPAR Pathway Are Involved in the Regulation of Flavor Compound Hexanal Content in Chinese Native Chickens. Genes 6 35205238
2021 Identification TRIM46 as a Potential Biomarker and Therapeutic Target for Clear Cell Renal Cell Carcinoma Through Comprehensive Bioinformatics Analyses. Frontiers in medicine 6 34881275
2024 Cannabinerol (CBNR) Influences Synaptic Genes Associated with Cytoskeleton and Ion Channels in NSC-34 Cell Line: A Transcriptomic Study. Biomedicines 3 38255294
2024 Genomic Effects of Biomechanical Loading in Adolescent Human Growth Plate Cartilage: A Pilot Study. Cartilage 3 39655393
2025 N-terminal truncating variants in CACNB1 cause a new congenital muscular disorder. European journal of human genetics : EJHG 2 41023410
2025 Identification of CACNB1 protein as an actionable therapeutic target for hepatocellular carcinoma via metabolic dysfunction analysis in liver diseases: An integrated bioinformatics and machine learning approach for precise therapy. International journal of biological macromolecules 1 40139615
2025 Identification of CaVβ1 Isoforms Required for Neuromuscular Junction Formation and Maintenance. Cells 1 40801641
2024 Decoding genetic and pathophysiological mechanisms in amyotrophic lateral sclerosis and primary lateral sclerosis: A comparative study of differentially expressed genes and implicated pathways in motor neuron disorders. Advances in protein chemistry and structural biology 1 38960473
2026 Hierarchical Network Organization and Dynamic Perturbation Propagation in Autism Spectrum Disorder: An Integrative Machine Learning and Hypergraph Analysis Reveals Super-Hub Genes and Therapeutic Targets. Biomedicines 0 41595671
2026 A comprehensive analysis of palmitoylation related genes in lung adenocarcinoma. Discover oncology 0 41697586
2026 Identification of myocardial contractility-related genes as regenerative targets and diagnostic biomarkers in coronary artery disease. Regenerative therapy 0 41969564
2025 PQBP1-dependent alternative RNA splicing underlies high calorie diet-induced cognitive impairment. bioRxiv : the preprint server for biology 0 40502014
2025 CACNB1 alleviates mepivacaine‑induced myocardial ischemia/reperfusion injury by promoting Nrf2 nuclear translocation. Molecular medicine reports 0 41416438

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