Affinage

CACNA1C

Voltage-dependent L-type calcium channel subunit alpha-1C · UniProt Q13936

Length
2221 aa
Mass
249.0 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CACNA1C encodes CaV1.2, the pore-forming α1C subunit of the L-type voltage-gated calcium channel, which serves as a central integrator of electrical excitability and intracellular calcium signaling across cardiac, vascular, and neuronal tissues. CaV1.2 resides within a macromolecular signaling complex containing β2-adrenergic receptors, PKA, adenylyl cyclase, PP2A, and calmodulin, enabling localized β-adrenergic regulation: PKA phosphorylation of Ser1700 maintains basal current and mediates adrenergic augmentation, while phosphorylation of Ser1928 displaces the β2AR to desensitize the channel (PMID:11441182, PMID:25368181, PMID:27103070). Channel activity is further tuned by CaMKII phosphorylation of the β2a subunit driving mode-2 gating, STIM1-mediated suppression at ER–plasma membrane junctions, Homer1-dependent coupling to RyR2, C-terminal oligomerization that amplifies Ca²⁺ influx, and developmental alternative splicing regulated by Fox proteins (PMID:20194790, PMID:20929813, PMID:17355963, PMID:22307641, PMID:19564422). Downstream, CaV1.2-mediated Ca²⁺ entry activates calcineurin/NFAT, CaMKII/HDAC, and NF-κB transcriptional programs controlling cardiac hypertrophy, craniofacial development, hair follicle stem cell quiescence, insulin secretion, and prefrontal cortical working memory (PMID:21111744, PMID:23549079, PMID:23752588, PMID:31355778, PMID:38776078).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2001 High

    Establishing that CaV1.2 operates within a pre-assembled macromolecular signaling complex containing β2AR, Gs, adenylyl cyclase, PKA, and PP2A resolved how β-adrenergic signaling achieves specificity and speed at the channel level.

    Evidence Co-immunoprecipitation and electrophysiology in hippocampal neurons

    PMID:11441182

    Open questions at the time
    • Stoichiometry and architecture of the complex remain undefined
    • Whether the same complex composition exists in cardiomyocytes versus neurons was not tested
  2. 2003 High

    Demonstrating that apocalmodulin pre-associates at the IQ motif and that mutation of IQ abolishes calcium-dependent inactivation established the molecular basis for CDI, a critical negative feedback mechanism.

    Evidence Peptide binding assays with CaM mutants and IQ-motif mutagenesis coupled with electrophysiology

    PMID:12944271

    Open questions at the time
    • Structural basis of the apoCaM-to-Ca²⁺/CaM conformational switch on the full-length channel was not resolved
    • Contribution of the N-lobe versus C-lobe in the intact channel context not fully delineated
  3. 2007 High

    Identifying Homer1 as a physical bridge between CaV1.2 and RyR2 that toggles excitation–contraction coupling between coupled and uncoupled states revealed a scaffolding mechanism for tuning Ca²⁺ release in smooth muscle.

    Evidence Split-GFP complementation assay, Homer1 knockout mice, functional Ca²⁺ release measurements

    PMID:17355963

    Open questions at the time
    • Whether Homer1 performs the same role in cardiac E-C coupling was not addressed
    • Structural details of the trimeric CaV1.2–Homer–RyR2 complex are unknown
  4. 2009 High

    Showing that α2δ-1 is essential for CaV1.2 surface expression in cerebral artery myocytes and that Fox splicing factors directly regulate CaV1.2 exon usage during cortical development established two independent mechanisms—auxiliary subunit scaffolding and alternative splicing—that control channel abundance and isoform diversity.

    Evidence shRNA knockdown with surface biotinylation and myogenic tone assay (α2δ-1); Fox protein gain/loss-of-function with minigene mutagenesis (Fox splicing)

    PMID:19564422 PMID:19797702

    Open questions at the time
    • Full catalog of tissue-specific splice isoforms and their functional consequences is incomplete
    • How α2δ-1 promotes surface trafficking mechanistically is unclear
  5. 2010 High

    Multiple studies converged to define key modulatory axes: CaMKII phosphorylation of β2a drives pathological mode-2 gating; STIM1 suppresses CaV1.2 at ER–PM junctions while activating Orai; Rem GTPase arrests channels in a low-open-probability state; and Ca²⁺ influx through CaV1.2 activates calcineurin/NFAT and CaMKII/HDAC to drive cardiac hypertrophy.

    Evidence Site-directed mutagenesis of β2a with electrophysiology (CaMKII); STIM1 SOAR domain co-IP and electrophysiology; Rem mutant analysis with gating current measurements; transgenic β2a-overexpressing mice with pharmacological pathway dissection

    PMID:20194790 PMID:20616312 PMID:20929813 PMID:21111744

    Open questions at the time
    • Whether STIM1 and CaMKII pathways interact at CaV1.2 is unknown
    • In vivo relevance of Rem-mediated gating arrest in disease states not established
    • Relative contribution of calcineurin versus CaMKII arms to hypertrophy in human heart unclear
  6. 2011 High

    BIN1 was identified as the trafficking scaffold delivering CaV1.2 to cardiac T-tubules, while dendritic CaV1.2 clusters in neurons were shown to be highly stable with dynamin-dependent endocytic maintenance, revealing tissue-specific trafficking paradigms.

    Evidence shRNA knockdown in cardiomyocytes with T-tubule fractionation and zebrafish morpholino (BIN1); FRAP and single-particle tracking of pHluorin-tagged CaV1.2 in hippocampal neurons

    PMID:21940459 PMID:22138472

    Open questions at the time
    • Molecular link between BIN1 and CaV1.2 (direct or indirect binding) not defined
    • Whether neuronal cluster stability depends on BIN1 or other scaffolds is untested
  7. 2012 High

    Demonstrating that CaV1.2 channels oligomerize via C-terminal tails to produce coordinated gating that amplifies Ca²⁺ influx—and that Timothy syndrome mutant channels can activate neighboring wild-type channels—established a cooperative gating mechanism with disease implications.

    Evidence Optogenetic-induced C-tail fusion, live-cell Ca²⁺ imaging, and patch-clamp in ventricular myocytes

    PMID:22307641

    Open questions at the time
    • Structural basis and stoichiometry of oligomeric CaV1.2 complexes not resolved
    • Whether oligomerization occurs in non-cardiac cell types is unknown
  8. 2013 High

    CaV1.2-mediated Ca²⁺ influx was shown to control craniofacial development through calcineurin signaling and hair follicle stem cell quiescence via regulation of follistatin-like 1, expanding the gene's functional repertoire beyond excitable tissues.

    Evidence Conditional mouse gain/loss-of-function with zebrafish rescue for mandibular development; conditional KO and Timothy syndrome knock-in mice with Fstl1 analysis for hair follicle biology

    PMID:23549079 PMID:23752588

    Open questions at the time
    • Mechanism by which CaV1.2 regulates Fstl1 in a voltage-independent manner is not resolved
    • Whether other non-excitable stem cells use CaV1.2 similarly is unknown
  9. 2014 High

    Ser1700Ala knock-in mice proved that PKA phosphorylation at Ser1700 is essential for basal L-type current maintenance and β-adrenergic augmentation, and its loss causes cardiac hypertrophy, pinpointing a single residue critical for cardiac physiology.

    Evidence Knock-in mouse model with patch-clamp and in vivo cardiac phenotyping

    PMID:25368181

    Open questions at the time
    • Whether Ser1700 phosphorylation is altered in human heart failure is untested
    • Interplay between Ser1700 and Ser1928 phosphorylation not fully dissected
  10. 2016 High

    PKA phosphorylation of Ser1928 was shown to displace the β2AR from CaV1.2 as a desensitization mechanism, with S1928A knock-in mice revealing dependence of prolonged theta-burst LTP on this interaction; concurrently, Rab25 was identified as controlling CaV1.2 surface density via recycling endosomes in vascular myocytes.

    Evidence S1928A knock-in mice with co-IP, electrophysiology, and LTP recordings; siRNA knockdown of Rab25 with surface biotinylation and pressurized artery assays

    PMID:27076616 PMID:27103070

    Open questions at the time
    • Whether Ser1928-dependent β2AR displacement occurs in cardiomyocytes is not established
    • Whether Rab25-dependent recycling operates in cardiac T-tubules is unknown
  11. 2017 High

    Temporal dissection of Cacna1c function revealed that embryonic deletion in forebrain glutamatergic neurons impairs cognition and plasticity while adult deletion improves cognitive flexibility and stress resilience, establishing developmental versus adult-specific roles.

    Evidence Embryonic versus adult conditional knockout mice with LTP recordings and behavioral phenotyping

    PMID:28696432

    Open questions at the time
    • Molecular basis for the opposite effects (developmental wiring versus acute signaling) is undefined
    • Cell-type-specific contributions within glutamatergic populations not resolved
  12. 2019 High

    β subunit binding to α1C was shown to be dispensable for CaV1.2 trafficking and basal cardiac function but required for β-adrenergic upregulation, fundamentally revising the textbook model of β subunit as a trafficking chaperone; separately, TDP-43 was identified as an upstream regulator of CaV1.2 expression critical for β-cell insulin secretion.

    Evidence β-subunit binding-incompetent α1C knock-in mice with electrophysiology and contractility assays; β-cell-specific Tardbp KO mice with CaV1.2 overexpression rescue

    PMID:30422117 PMID:31355778

    Open questions at the time
    • How CaV1.2 reaches the surface without β subunit assistance is mechanistically unexplained
    • Whether TDP-43 regulates CaV1.2 transcriptionally or post-transcriptionally is not fully resolved
  13. 2024 High

    Localization of CaV1.2 to dendritic spines near smooth ER in primate prefrontal cortex layer III pyramidal neurons, together with in vivo pharmacology showing both blockade and excessive activation reduce working-memory-related firing, established CaV1.2 as an inverted-U regulator of prefrontal network function.

    Evidence Electron/light microscopy, transcriptomics, and in vivo pharmacology with single-unit recording during working memory in macaques

    PMID:38776078

    Open questions at the time
    • Precise signaling cascade from CaV1.2 to SK3 activation in primate spines not fully delineated
    • Whether CACNA1C psychiatric risk variants alter this spine-level mechanism is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structural model of the full-length CaV1.2 macromolecular complex (with β2AR, PKA, CaM, and scaffolding partners) and the mechanism by which CaV1.2 operates in a voltage-independent mode in non-excitable cells remain unresolved.
  • No cryo-EM or crystal structure of the intact CaV1.2 signaling complex
  • Voltage-independent signaling mechanism in stem cells is molecularly undefined
  • How CACNA1C psychiatric risk variants alter channel function or expression at the molecular level is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 6 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-112316 Neuronal System 4 R-HSA-397014 Muscle contraction 4 R-HSA-382551 Transport of small molecules 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1266738 Developmental Biology 2
Partners
ADRB2BIN1CACNA2D1CACNB2CALM1CAMK2AHOMER1STIM1
Complex memberships
CaV1.2–Homer1–RyR2 coupling complexCaV1.2–STIM1–Orai1 junction complexβ2AR–CaV1.2–PKA–AC–PP2A signaling complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 The β2 adrenergic receptor (β2AR) is directly and physically associated with CaV1.2 (CACNA1C) in a macromolecular signaling complex that also contains a G protein, adenylyl cyclase, cAMP-dependent protein kinase (PKA), and phosphatase PP2A, enabling highly localized and specific signal transduction from the receptor to the channel in hippocampal neurons. Co-immunoprecipitation, biochemical reconstitution, and electrophysiological recording in hippocampal neurons Science High 11441182
2010 STIM1, activated by store depletion, strongly suppresses CaV1.2 (CACNA1C) channel activity while simultaneously activating Orai channels; both effects are mediated by the SOAR domain of STIM1, which physically interacts with CaV1.2 within discrete ER/plasma membrane junctions containing both CaV1.2 and Orai1. Co-immunoprecipitation, co-localization imaging, electrophysiology, mutational analysis of STIM1 SOAR domain Science High 20929813
2003 Apocalmodulin (apoCaM) binds with higher affinity to the C-IQ region (around the IQ motif) of the CaV1.2 α1 subunit C-terminus; Ca2+ binding to the C-lobe of CaM is enhanced by the IQ peptide, and mutation of the IQ motif (Ile/Gln to Ala) destroys Ca2+-dependent inactivation and reduces apoCaM interaction, supporting a model where pre-associated apoCaM at IQ enables rapid CDI upon Ca2+ binding. Peptide binding assays, CaM mutant analysis, mutagenesis of IQ motif in full-length channel with electrophysiology Biophysical Journal High 12944271
2010 CaMKII binds to and phosphorylates the CaV1.2 β2a subunit at Leu493 and Thr498, respectively; these interactions are required for CaMKII-dependent high-activity 'mode 2' gating of CaV1.2, early afterdepolarizations, Ca2+ overload, and premature cardiomyocyte death in paced adult rabbit ventricular myocytes. Site-directed mutagenesis of β2a subunit (T498A, L493A), patch-clamp electrophysiology, overexpression in adult rabbit cardiomyocytes PNAS High 20194790
2012 CaV1.2 channels form clusters in ventricular myocytes and physically interact via their C-terminal tails, allowing coordinated gating (oligomerization) that amplifies Ca2+ influx and excitation-contraction coupling; gain-of-function Timothy syndrome channels (CaV1.2-TS) increase the activity of adjoining WT channels through this interaction. Optogenetic-induced fusion of channel C-tails, live-cell Ca2+ imaging, patch-clamp in ventricular myocytes PNAS High 22307641
2014 Phosphorylation of CaV1.2 at Ser1700 by PKA is essential for maintaining basal L-type Ca2+ current in cardiomyocytes and is required for the incremental increase in current elicited by β-adrenergic stimulation; Ser1700Ala knock-in mice develop cardiac hypertrophy and reduced exercise capacity. Ser1700Ala knock-in mouse model, patch-clamp in cardiomyocytes, in vivo cardiac function analysis PNAS High 25368181
2016 PKA-mediated phosphorylation of CaV1.2 at Ser1928 (located within the β2AR binding site, residues 1923-1942) displaces the β2AR from CaV1.2 upon β-adrenergic stimulation, rendering the channel refractory to further β-adrenergic regulation for several minutes; this mechanism is absent in S1928A knock-in mice, and LTP induced by prolonged theta tetanus depends on this CaV1.2/β2AR interaction. S1928A knock-in mice, co-immunoprecipitation, electrophysiology, LTP recordings The EMBO Journal High 27103070
2009 The α2δ-1 subunit is the sole α2δ isoform in cerebral artery myocytes and is essential for plasma membrane expression of CaV1.2 α1 subunits; α2δ-1 knockdown reduces surface CaV1.2, decreases intracellular Ca2+, and inhibits pressure-induced vasoconstriction (myogenic tone). shRNA knockdown, surface biotinylation, patch-clamp, pressurized artery myogenic tone assay Circulation Research High 19797702
2011 BIN1 (bridging integrator 1), a membrane scaffolding protein, is required for trafficking of CaV1.2 to cardiac T-tubules; BIN1 knockdown in mouse cardiomyocytes decreases surface CaV1.2, impairs Ca2+ transients, and BIN1 is significantly reduced in failing human cardiomyocytes, which correlates with reduced peripheral CaV1.2. shRNA knockdown in mouse cardiomyocytes, immunofluorescence, patch-clamp, T-tubule fractionation, zebrafish morpholino knockdown Heart Rhythm High 22138472
2010 Rem GTPase inhibits cardiac CaV1.2 channels primarily by arresting surface channels in a low open-probability gating mode (not by reducing channel number); this inhibition requires GTP binding by Rem but not membrane targeting of the nucleotide-binding domain, and prevents PKA-mediated upregulation of ICa,L without affecting PKA modulation of IKs. Adenoviral overexpression in adult guinea pig cardiomyocytes, patch-clamp, gating current measurement, Rem mutant analysis Circulation Research High 20616312
2007 Homer1 mediates a dynamic physical interaction between CaV1.2 and RyR2 in smooth muscle; Homer1b/c promotes coupling (reduces responsiveness to membrane depolarization) while Homer1a uncouples CaV1.2 and RyR2 to enhance responsiveness, defining a two-state model of E-C coupling; deletion of Homer1 in mice impairs urinary bladder E-C coupling. Split-GFP complementation assay, Homer1 knockout mice, functional Ca2+ release measurements Journal of Biological Chemistry High 17355963
2009 Fox family splicing regulators (Fox1, Fox2) directly control alternative splicing of CaV1.2 exons 9* and 33 during cortical development by binding Fox binding elements in adjacent introns; Fox proteins repress exon 9* inclusion and enhance exon 33 inclusion, with opposite developmental trajectories, tuning CaV1.2 electrophysiological properties. shRNA knockdown and overexpression of Fox proteins, minigene reporters with mutagenesis of Fox binding elements, endogenous CaV1.2 splicing analysis Molecular and Cellular Biology High 19564422
2011 Truncation of murine CaV1.2 at Asp-1904 (Stop mutation) reduces CaV1.2 expression and current in cardiac (but not smooth muscle) cells due to proteasomal degradation of the cardiac splice variant (HK1), leading to heart failure after birth; the smooth muscle variant (LK1) with the same truncation is stable and maintains normal current. Knock-in mouse model with stop codons at Asp-1904, patch-clamp in cardiomyocytes and HEK293 cells, proteasome inhibitor rescue Journal of Biological Chemistry High 21832054
2010 Increasing Ca2+ influx through CaV1.2 (via β2a subunit overexpression) is sufficient to induce pathological cardiac hypertrophy through calcineurin/NFAT and CaMKII/HDAC pathways; blocking CaV1.2 current, intracellular Ca2+, calcineurin, CaMKII, or SERCA abolishes these hypertrophic effects. Transgenic mouse overexpression of β2a subunit, adenoviral overexpression in cultured cardiomyocytes, pharmacological pathway inhibition, NFAT/HDAC translocation assays Journal of Molecular and Cellular Cardiology High 21111744
2013 CaV1.2 is expressed in pharyngeal arch cells giving rise to jaw primordia; Ca2+ influx through CaV1.2 regulates mandibular development by controlling cellular hypertrophy and hyperplasia via the calcineurin signaling pathway, as shown by gain- and loss-of-function in mouse and zebrafish models. Conditional mouse gain/loss-of-function, zebrafish knockdown/rescue, pharmacological calcineurin inhibition, craniofacial measurements Journal of Clinical Investigation High 23549079
2013 In hair follicle stem cells, CaV1.2 acts in a state-dependent (voltage-independent) manner to regulate production of the BMP inhibitor follistatin-like1 (Fstl1), controlling stem cell quiescence and hair follicle anagen entry; Timothy syndrome CaV1.2 acts dominant-negatively to delay anagen, and L-type channel blockers act through CaV1.2 to induce anagen. Conditional knockout and Timothy syndrome knock-in mice, pharmacological L-type channel blockade, Fstl1 expression analysis, hair follicle stem cell functional assays Genes & Development High 23752588
2011 In hippocampal neurons, dendritic CaV1.2 channels reside in stable clusters with highly confined lateral mobility (diffusion coefficient ~0.005 µm²/s) maintained by dynamin-dependent endocytosis; ~30% of channels exchange between confined and diffusive states, and strong depolarization does not alter cluster stability or diffusion coefficients. FRAP with superecliptic pHluorin-tagged CaV1.2, pulse-chase labeling, single particle tracking (SPT), dynamin inhibition Journal of Neuroscience High 21940459
2019 Cardiac CaV1.2 α1C subunits lacking β-subunit binding can traffic to the sarcolemma and sustain normal excitation-contraction coupling in adult cardiomyocytes in vivo, but cannot be stimulated by β-adrenergic pathway agonists; thus β subunits are required for β-adrenergic regulation and positive inotropy, but dispensable for CaV1.2 trafficking and basal function. Transgenic knock-in of β-subunit binding-incompetent α1C in adult mice, patch-clamp, viral delivery of β-subunit-sequestering peptide, cardiac contractility assay Journal of Clinical Investigation High 30422117
2015 Homer proteins (specifically Homer1) mediate the physical association between STIM1 and the CaV1.2 α1 subunit; impairment of Homer function (by PPKKFR peptide or siRNA Homer1 knockdown) reduces STIM1–CaV1.2 co-immunoprecipitation and alters nifedipine-sensitive Ca2+ entry upon store depletion. Co-immunoprecipitation, siRNA knockdown of Homer1, PPKKFR competitive peptide, Ca2+ measurement in HEK-293 cells expressing CaV1.2 subunits Biochimica et Biophysica Acta Medium 25712868
2010 α5β1-integrin physically associates with CaV1.2 in a fibronectin-dependent manner in arterial smooth muscle and HEK293-T cells; this interaction requires CaV1.2 C-terminal residues Ser1901, Tyr2122, and two proline-rich domains, and c-Src mediates current potentiation following integrin engagement. Co-immunoprecipitation, site-directed mutagenesis of CaV1.2 C-terminus, patch-clamp, confocal co-localization American Journal of Physiology - Cell Physiology Medium 21178109
2016 CaV1.2 channels in cerebral artery myocytes are controlled by the small GTPase Rab25, which promotes recycling endosome-mediated surface expression; Rab25 knockdown reduces surface and intracellular CaV1.2 abundance via lysosomal and proteasomal degradation, decreasing CaV1.2 current density and pressure/depolarization-induced vasoconstriction. siRNA knockdown, surface biotinylation, immunoFRET microscopy, patch-clamp, pressurized artery myogenic tone assay American Journal of Physiology - Cell Physiology Medium 27076616
2010 IP3R-mediated SR Ca2+ release elevates mitochondrial Ca2+, inducing mitochondrial ROS generation that activates NF-κB, which in turn stimulates CaV1.2 channel transcription in cerebral artery myocytes; blocking IP3R, the mitochondrial electron transport chain, antioxidants, or NF-κB knockdown all reduce CaV1.2 expression and cause vasodilation. siRNA knockdown of NF-κB subunits, pharmacological inhibitors of IP3R/ETC/antioxidants, reporter assays, qPCR, functional vasoconstriction assays Circulation Research Medium 20616314
2009 KChIP2 directly interacts with the N-terminus of CaV1.2 and functionally modulates the cardiac L-type Ca2+ current (ICa,L); in KChIP2 knockout mice, ICa,L is decreased and the CACNB2 (β2 subunit) is transcriptionally upregulated. Co-immunoprecipitation, KChIP2 knockout mice, patch-clamp, gene-chip and real-time PCR Channels Medium 19713767
2016 NFAT5 binds to the consensus sequence TGGAAGCGTTC in the promoter of CACNA1C and activates its transcription; siRNA-mediated Nfat5 knockdown suppresses Cacna1c expression and decreases L-type Ca2+ current in neonatal cardiomyocytes; morpholino knockdown of nfat5 in zebrafish impairs cacna1c expression and results in non-contractile ventricle that is rescued by cacna1c or nfat5 overexpression. Promoter reporter assays, ChIP-like binding analysis, siRNA knockdown, patch-clamp, zebrafish morpholino knockdown and rescue Journal of Molecular Medicine Medium 27368804
2015 A truncated CaV1.2 splice variant generated by inclusion of novel exon 33L (frameshift, C-terminal truncation) acts as a dominant-negative on full-length CaV1.2 (and CaV1.3 but not CaV3.2) by enhancing proteasomal degradation via the ubiquitin-proteasome system, requiring β-subunit interaction; human exon 33L produces a functional but low-conductance channel due to a one-nucleotide insertion allowing in-frame translation. Electrophysiology in HEK293 cells (co-expression of truncated and WT channels), proteasome inhibitor treatment, mutagenesis, ubiquitin-proteasome pathway analysis Journal of Biological Chemistry Medium 25694430
2021 Depolarization activates PKA type II (PKA-II) in nociceptors via Ca2+ influx through CaV1.2 channels; PKA-II then phosphorylates CaV1.2 Ser1928, increasing channel gating in a feed-forward mechanism, while calcineurin dephosphorylates Ser1928; this drives sensitization of Ca2+ currents and peripheral hyperalgesia. High-content screening microscopy, patch-clamp, pharmacological inhibitors, in vivo behavioral hyperalgesia assay Journal of Cell Biology Medium 34431981
2019 TDP-43 (encoded by TARDBP) regulates CaV1.2 expression; loss of TDP-43 in β cells and in β cell-specific Tardbp knockout mice downregulates CaV1.2, inhibiting L-type Ca2+-channel-mediated exocytosis and reducing early-phase insulin secretion; overexpression of CaV1.2 rescues early-phase insulin secretion in TDP-43-depleted cells. β cell-specific Tardbp knockout mice, shRNA knockdown in MIN6 cells, CaV1.2 overexpression rescue, electrophysiology, insulin secretion assays Journal of Clinical Investigation High 31355778
2017 Cacna1c in the VTA (but not NAc) is required for behavioral sensitization to the DAT antagonist GBR12909; constitutive Cacna1c haploinsufficiency impairs DAT inhibition-induced dopamine release sensitivity in the NAc as measured by fast-scan cyclic voltammetry, demonstrating a presynaptic role for Cav1.2 in mesolimbic dopamine function. Conditional knockout mice (VTA-specific), fast-scan cyclic voltammetry, locomotor sensitization behavioral assay Genes, Brain, and Behavior Medium 28186690
2022 Increased Ca2+ influx through CaV1.2 within aortic valve interstitial cells (VICs) drives calcific aortic valve disease (CAVD) by activating chondrogenic and osteogenic transcriptional programs and myofibroblast activation; chronic verapamil (CaV1.2 antagonist) treatment slows lesion progression in vivo. Transgenic mouse model overexpressing CaV1.2 in VICs, VIC cell culture, pharmacological CaV1.2 block with verapamil, transcriptional analysis JCI Insight Medium 35104251
2024 In layer III pyramidal cells of the primate dorsolateral prefrontal cortex, CaV1.2 (CACNA1C) is concentrated in dendritic spines near the calcium-storing smooth ER and co-expressed with GRIN2B and KCNN3 (SK3); CaV1.2 activity influences memory-related neuronal firing, with either blockade or excessive activation (via β1-adrenoceptors triggering SK3 channel opening) both reducing neuronal firing needed for working memory. Transcriptomic analysis of primate/human dorsolateral PFC, electron and light microscopy protein expression, in vivo pharmacological manipulation with electrophysiology during working memory task in macaques JAMA Psychiatry High 38776078
2016 miR-29a-3p directly targets the 3'-UTR of CACNA1C, negatively regulating its mRNA and protein expression; overexpression of miR-29a-3p in cardiomyocytes reduces ICa,L, mimicking the electrical remodeling seen in atrial fibrillation. Luciferase 3'-UTR reporter assay, transfection in cardiomyocytes, patch-clamp (ICa,L recording), Western blot Medical Science Monitor Medium 27341015
2017 Embryonic deletion of Cacna1c in forebrain glutamatergic neurons impairs synaptic plasticity and cognition and increases stress susceptibility, whereas adult deletion of Cacna1c in the same neurons improves cognitive flexibility and induces stress resilience, demonstrating a temporally distinct and opposite role for Cav1.2 in development versus adulthood. Conditional knockout mice (embryonic vs. adult forebrain glutamatergic neuron-specific), behavioral testing, synaptic plasticity (LTP) recordings Molecular Psychiatry High 28696432

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 A beta2 adrenergic receptor signaling complex assembled with the Ca2+ channel Cav1.2. Science (New York, N.Y.) 439 11441182
2010 The calcium store sensor, STIM1, reciprocally controls Orai and CaV1.2 channels. Science (New York, N.Y.) 293 20929813
1978 Premature of chromosome condensation in a ts DNA- mutant of BHK cells. Cell 226 719750
2012 CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease. Progress in neurobiology 222 22705413
1986 Site specificity of casein kinase-2 (TS) from rat liver cytosol. A study with model peptide substrates. European journal of biochemistry 196 3464423
2011 BIN1 is reduced and Cav1.2 trafficking is impaired in human failing cardiomyocytes. Heart rhythm 134 22138472
2017 Cross-disorder risk gene CACNA1C differentially modulates susceptibility to psychiatric disorders during development and adulthood. Molecular psychiatry 122 28696432
2018 CACNA1C: Association With Psychiatric Disorders, Behavior, and Neurogenesis. Schizophrenia bulletin 116 29982775
2019 Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain. Molecular psychiatry 107 31695164
2010 CaV1.2 beta-subunit coordinates CaMKII-triggered cardiomyocyte death and afterdepolarizations. Proceedings of the National Academy of Sciences of the United States of America 106 20194790
2009 Activating systemic autoimmunity: B's, T's, and tolls. Current opinion in immunology 106 19800208
2012 Ca2+ signaling amplification by oligomerization of L-type Cav1.2 channels. Proceedings of the National Academy of Sciences of the United States of America 103 22307641
2005 Splicing for alternative structures of Cav1.2 Ca2+ channels in cardiac and smooth muscles. Cardiovascular research 100 16051206
2010 Calcium influx through Cav1.2 is a proximal signal for pathological cardiomyocyte hypertrophy. Journal of molecular and cellular cardiology 92 21111744
2019 Polypeptide GalNAc-Ts: from redundancy to specificity. Current opinion in structural biology 88 30703750
2014 Long QT syndrome type 8: novel CACNA1C mutations causing QT prolongation and variant phenotypes. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 79 24728418
2003 Apocalmodulin and Ca2+ calmodulin-binding sites on the CaV1.2 channel. Biophysical journal 78 12944271
2009 CaV1.2 channelopathies: from arrhythmias to autism, bipolar disorder, and immunodeficiency. Pflugers Archiv : European journal of physiology 77 19916019
2000 Simultaneous estimation of T(G2+M), T(S), and T(pot) using single sample dynamic tumor data from bivariate DNA-thymidine analogue cytometry. Cytometry 77 10942890
2009 Smooth muscle cell alpha2delta-1 subunits are essential for vasoregulation by CaV1.2 channels. Circulation research 68 19797702
2014 Basal and β-adrenergic regulation of the cardiac calcium channel CaV1.2 requires phosphorylation of serine 1700. Proceedings of the National Academy of Sciences of the United States of America 66 25368181
2009 Developmental control of CaV1.2 L-type calcium channel splicing by Fox proteins. Molecular and cellular biology 66 19564422
2019 Approval of First CAR-Ts: Have we Solved all Hurdles for ATMPs? Cell medicine 65 32634192
2010 Mitochondria control functional CaV1.2 expression in smooth muscle cells of cerebral arteries. Circulation research 62 20616314
2016 Phosphorylation of Cav1.2 on S1928 uncouples the L-type Ca2+ channel from the β2 adrenergic receptor. The EMBO journal 60 27103070
2013 Calcium influx through L-type CaV1.2 Ca2+ channels regulates mandibular development. The Journal of clinical investigation 59 23549079
2015 Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease. Circulation. Cardiovascular genetics 56 26553695
2015 Schizophrenia Related Variants in CACNA1C also Confer Risk of Autism. PloS one 54 26204268
2019 Cardiac CaV1.2 channels require β subunits for β-adrenergic-mediated modulation but not trafficking. The Journal of clinical investigation 52 30422117
2019 TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets. The Journal of clinical investigation 52 31355778
2015 MiR-103 inhibits osteoblast proliferation mainly through suppressing Cav1.2 expression in simulated microgravity. Bone 52 25868801
2011 Surface traffic of dendritic CaV1.2 calcium channels in hippocampal neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 52 21940459
2009 CACNA1C gene polymorphisms, cardiovascular disease outcomes, and treatment response. Circulation. Cardiovascular genetics 51 20031608
2016 The Neuropsychiatric Disease-Associated Gene cacna1c Mediates Survival of Young Hippocampal Neurons. eNeuro 50 27066530
2010 Molecular mechanisms, and selective pharmacological rescue, of Rem-inhibited CaV1.2 channels in heart. Circulation research 50 20616312
2010 Assembly of Q{beta} viral RNA polymerase with host translational elongation factors EF-Tu and -Ts. Proceedings of the National Academy of Sciences of the United States of America 49 20798060
2012 CaV1.2 sparklets in heart and vascular smooth muscle. Journal of molecular and cellular cardiology 46 23220157
2007 Ca2+ signaling in microdomains: Homer1 mediates the interaction between RyR2 and Cav1.2 to regulate excitation-contraction coupling. The Journal of biological chemistry 43 17355963
1992 The spoIIN279(ts) mutation affects the FtsA protein of Bacillus subtilis. Biochimie 43 1391048
2020 Disruption of Cav1.2-mediated signaling is a pathway for ketamine-induced pathology. Nature communications 42 32859919
2000 Deoxyuridine triphosphatase (dUTPase) expression and sensitivity to the thymidylate synthase (TS) inhibitor ZD9331. British journal of cancer 42 10952785
2014 Analysis of ANK3 and CACNA1C variants identified in bipolar disorder whole genome sequence data. Bipolar disorders 41 24716743
1992 Relation between the convergence temperatures Th* and Ts* in protein unfolding. Proceedings of the National Academy of Sciences of the United States of America 41 1496007
2016 Underexpression of CACNA1C Caused by Overexpression of microRNA-29a Underlies the Pathogenesis of Atrial Fibrillation. Medical science monitor : international medical journal of experimental and clinical research 39 27341015
2004 Thymidylate synthetase (TS) genotype and TS/dihydropyrimidine dehydrogenase mRNA level as an indicator in determining chemosensitivity to 5-fluorouracil in advanced gastric carcinoma. Anticancer research 37 15330198
2021 TS-HDS and FGFR3 antibodies in small fiber neuropathy and Dysautonomia. Muscle & nerve 35 33792960
2016 Common variants in CACNA1C and MDD susceptibility: A comprehensive meta-analysis. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 35 27260792
2015 Genetic analysis of SNPs in CACNA1C and ANK3 gene with schizophrenia: A comprehensive meta-analysis. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 33 26227746
2017 Decreased Nucleus Accumbens Expression of Psychiatric Disorder Risk Gene Cacna1c Promotes Susceptibility to Social Stress. The international journal of neuropsychopharmacology 31 28165117
2003 Expression of uracil DNA glycosylase (UDG) does not affect cellular sensitivity to thymidylate synthase (TS) inhibition. European journal of cancer (Oxford, England : 1990) 31 12565992
2024 Key Roles of CACNA1C/Cav1.2 and CALB1/Calbindin in Prefrontal Neurons Altered in Cognitive Disorders. JAMA psychiatry 29 38776078
2020 Cav1.2 channelopathies causing autism: new hallmarks on Timothy syndrome. Pflugers Archiv : European journal of physiology 29 32621084
2015 Homer proteins mediate the interaction between STIM1 and Cav1.2 channels. Biochimica et biophysica acta 29 25712868
2011 Truncation of murine CaV1.2 at Asp-1904 results in heart failure after birth. The Journal of biological chemistry 29 21832054
2007 Regulation of Cav1.2 current: interaction with intracellular molecules. Journal of pharmacological sciences 29 17409629
2019 CACNA1C (rs1006737) may be a susceptibility gene for schizophrenia: An updated meta-analysis. Brain and behavior 28 31033230
2010 Spatial association of the Cav1.2 calcium channel with α5β1-integrin. American journal of physiology. Cell physiology 28 21178109
2012 Role of PKC and CaV1.2 in detrusor overactivity in a model of obesity associated with insulin resistance in mice. PloS one 27 23144896
2017 Reduced levels of Cacna1c attenuate mesolimbic dopamine system function. Genes, brain, and behavior 26 28186690
2013 State-dependent signaling by Cav1.2 regulates hair follicle stem cell function. Genes & development 26 23752588
2017 Identification and mapping of ts (tender spines), a gene involved in soft spine development in Cucumis sativus. TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik 25 29116330
2009 The do's and don'ts of p53 isoforms. Biological chemistry 25 19453282
2023 CACNA1C-Related Channelopathies. Handbook of experimental pharmacology 24 36598608
2021 Inhibiting microRNA-155 attenuates atrial fibrillation by targeting CACNA1C. Journal of molecular and cellular cardiology 24 33636223
2017 P53 represses pyrimidine catabolic gene dihydropyrimidine dehydrogenase (DPYD) expression in response to thymidylate synthase (TS) targeting. Scientific reports 24 28851987
2022 CAR-Ts: new perspectives in cancer therapy. FEBS letters 23 34978080
2020 Dopamine D1R-neuron cacna1c deficiency: a new model of extinction therapy-resistant post-traumatic stress. Molecular psychiatry 22 32332995
2016 Von Willebrand disease - the 'Dos' and 'Don'ts' in surgery. European journal of haematology 22 27622750
2005 Expression of multiple CaV1.2 transcripts in rat tissues mediated by different promoters. Cell calcium 22 15755491
2003 Surgical do's and don'ts of corneal dystrophies. Current opinion in ophthalmology 21 12888715
2019 Sex-dependent effects of Cacna1c haploinsufficiency on behavioral inhibition evoked by conspecific alarm signals in rats. Progress in neuro-psychopharmacology & biological psychiatry 20 31862418
2016 NFAT5-mediated CACNA1C expression is critical for cardiac electrophysiological development and maturation. Journal of molecular medicine (Berlin, Germany) 20 27368804
2014 Genetic variation in CACNA1C affects neural processing in major depression. Journal of psychiatric research 20 24612926
2009 Effects of CYP3A5, MDR1 and CACNA1C polymorphisms on the oral disposition and response of nimodipine in a Chinese cohort. European journal of clinical pharmacology 20 19205682
2022 Bipolar-associated miR-499-5p controls neuroplasticity by downregulating the Cav1.2 subunit CACNB2. EMBO reports 19 35969184
2019 Genetic Variation in the Psychiatric Risk Gene CACNA1C Modulates Reversal Learning Across Species. Schizophrenia bulletin 19 30304534
2017 Genes Involved in Neurodevelopment, Neuroplasticity, and Bipolar Disorder: CACNA1C, CHRNA1, and MAPK1. Neuropsychobiology 19 28494468
2015 Extracellular overexpression of chitosanase from Bacillus sp. TS in Escherichia coli. Applied biochemistry and biotechnology 19 25637506
1975 Complementation of defective reovirus by ts mutants. Journal of virology 19 1117490
2020 Development of a novel thymidylate synthase (TS) inhibitor capable of up-regulating P53 expression and inhibiting angiogenesis in NSCLC. Journal of advanced research 18 33133686
2014 Direct evidence of an elongation factor-Tu/Ts·GTP·Aminoacyl-tRNA quaternary complex. The Journal of biological chemistry 18 24990941
2017 A mutation in the CACNA1C gene leads to early repolarization syndrome with incomplete penetrance: A Chinese family study. PloS one 17 28493952
2015 Alternative splicing generates a novel truncated Cav1.2 channel in neonatal rat heart. The Journal of biological chemistry 17 25694430
2009 Silencing of Cav1.2 gene in neonatal cardiomyocytes by lentiviral delivered shRNA. Biochemical and biophysical research communications 17 19422800
2022 Role of CACNA1C in Brugada syndrome: Prevalence and phenotype of probands referred for genetic testing. Heart rhythm 16 34999275
2009 Transcriptional and electrophysiological consequences of KChIP2-mediated regulation of CaV1.2. Channels (Austin, Tex.) 16 19713767
2009 Beta-adrenergic modulation of arrhythmogenesis and identification of targeted sites of antiarrhythmic therapy in Timothy (LQT8) syndrome: a theoretical study. American journal of physiology. Heart and circulatory physiology 16 19855067
2019 Allicin disrupts cardiac Cav1.2 channels via trafficking. Pharmaceutical biology 15 30929547
2019 Dysfunctional Cav1.2 channel in Timothy syndrome, from cell to bedside. Experimental biology and medicine (Maywood, N.J.) 15 31324123
2016 Rab25 influences functional Cav1.2 channel surface expression in arterial smooth muscle cells. American journal of physiology. Cell physiology 15 27076616
2015 Evaluating the association between CACNA1C rs1006737 and schizophrenia risk: A meta-analysis. Asia-Pacific psychiatry : official journal of the Pacific Rim College of Psychiatrists 15 25588813
1993 Cell-type- and promoter-dependent ts phenotype of p53 Val135. Oncogene 15 8247545
1986 High temperature induction of a stringent response in the dnaK(Ts) and dnaJ(Ts) mutants of Escherichia coli. Journal of biochemistry 15 2427506
2023 Regulation of Cardiac Cav1.2 Channels by Calmodulin. International journal of molecular sciences 14 37047381
2022 Increased Ca2+ influx through CaV1.2 drives aortic valve calcification. JCI insight 14 35104251
2022 A Cross-Sectional Study of the Neuropsychiatric Phenotype of CACNA1C-Related Disorder. Pediatric neurology 14 36436328
2021 Depolarization induces nociceptor sensitization by CaV1.2-mediated PKA-II activation. The Journal of cell biology 14 34431981
2018 The effect of psychosis associated CACNA1C, and its epistasis with ZNF804A, on brain function. Genes, brain, and behavior 14 30079586
2017 Deletion of psychiatric risk gene Cacna1c impairs hippocampal neurogenesis in cell-autonomous fashion. Glia 14 28230278
2017 Emerging Role of CaV1.2 Channels in Proliferation and Migration in Distinct Cancer Cell Lines. Oncology 14 28355609