Affinage

CACNA1E

Voltage-dependent R-type calcium channel subunit alpha-1E · UniProt Q15878

Length
2313 aa
Mass
261.7 kDa
Annotated
2026-06-09
100 papers in source corpus 24 papers cited in narrative 24 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

CACNA1E encodes the pore-forming α1E subunit of CaV2.3, a high-voltage-activated R-type calcium channel that couples membrane depolarization to Ca2+ entry across neuronal, endocrine, cardiac, and germ-cell membranes, defined pharmacologically by relative dihydropyridine/ω-toxin resistance and partial Ni2+ and SNX-482 sensitivity (PMID:7719708). Channel gating is set by discrete structural determinants: residue R378 in the I-II linker AID controls voltage-dependent inactivation (PMID:11159396), hydrophobic residues of the S6 segments (the IVS6 VAVIM motif and equivalent positions) stabilize the closed state (PMID:17660294), and the AID anchor residues Trp13/Ile14 dock the auxiliary CaVβ subunit through a hydrophobic leucine quartet in the β GK domain that governs plasma-membrane density (PMID:15507442, PMID:22846999), with membrane-anchored β2a/β2e splice variants sustaining channel availability during repetitive firing (PMID:35792082). The cytosolic II-III loop integrates G-protein and kinase signaling: an arginine-rich motif mediates PKC-dependent stimulation and recruits hsp70 (PMID:15147300, PMID:16543726), while Gαq/11-coupled muscarinic and NK1 receptors drive PKC stimulation alongside Gβγ- and Gαq/11-mediated inhibition (PMID:14742680, PMID:17050807). The channel is further regulated by CDKL5 phosphorylation, which slows inactivation and tunes excitability (PMID:38081835), by GABAB-receptor/c-Src signaling at C-terminal tyrosines Y1761/Y1765 and by KCTD8/KCTD12b auxiliary subunits at presynaptic active zones (PMID:24688019, PMID:33913808), and by FMRP-mediated translational repression that is relieved by group I mGluR activation (PMID:31350260). Physiologically, CaV2.3 controls second-phase insulin secretion (PMID:15630454), reticular-thalamic oscillatory bursting and seizure/excitotoxicity susceptibility (PMID:17376845, PMID:21482359), dopaminergic neuron vulnerability in Parkinson models (PMID:31704946), sperm acrosome exocytosis (PMID:24525187), prenatal cardiac rhythmicity (PMID:14976402), axon-to-dendrite identity conversion (PMID:21602796), and nociception (PMID:35050960, PMID:28614186). CDKL5 substrate work mechanistically links CACNA1E gain-of-function developmental epileptic encephalopathy (DEE69) to CDKL5 deficiency disorder (PMID:38081835).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1994 High

    Establishing that α1E forms a distinct high-voltage-activated channel with a unique pharmacological and Ni2+-sensitivity signature defined CaV2.3 as a separate channel class and showed auxiliary subunits reshape its kinetics.

    Evidence Cloned cDNA expressed in Xenopus oocytes with whole-cell electrophysiology, pharmacological profiling, and β/α2 co-expression

    PMID:7719708

    Open questions at the time
    • Native channel identity in tissue not yet addressed
    • Structural basis of subunit modulation undefined
  2. 2001 High

    Identifying R378 in the AID as a determinant of voltage-dependent inactivation localized inactivation gating to the I-II linker.

    Evidence Site-directed mutagenesis and whole-cell patch-clamp in Xenopus oocytes

    PMID:11159396

    Open questions at the time
    • Does not resolve full conformational pathway of inactivation
    • Interaction with S6 gating elements not established here
  3. 2004 High

    Mapping the CaVβ anchor to Trp13/Ile14 of the AID and the II-III loop arginine-rich motif to PKC stimulation defined the structural interfaces for auxiliary modulation and kinase regulation.

    Evidence Alanine/site-directed mutagenesis, CaVβ overlay binding, PKC inhibitor pharmacology, and electrophysiology in HEK cells with homology modeling

    PMID:14742680 PMID:15147300 PMID:15507442

    Open questions at the time
    • Endogenous PKC isoform specificity in neurons not resolved
    • In vivo relevance of these interfaces untested
  4. 2004 Medium

    Demonstrating CaV2.3 requirement for regular prenatal heartbeat extended its role beyond neurons to embryonic cardiac pacemaking.

    Evidence Multielectrode array recordings of embryonic CaV2.3-/- and WT hearts with SNX-482 pharmacology

    PMID:14976402

    Open questions at the time
    • Cellular mechanism linking CaV2.3 to rhythm stabilization unclear
    • Single lab, embryonic stage only
  5. 2005 High

    Genetic and pharmacological ablation tied CaV2.3 specifically to second-phase insulin secretion, assigning it a defined endocrine function.

    Evidence CaV2.3 knockout mice, dynamic insulin assays, SNX-482, beta-cell Ca2+ imaging and capacitance measurements

    PMID:15630454

    Open questions at the time
    • Molecular coupling to granule recruitment not fully defined
    • Human beta-cell relevance not tested
  6. 2006 High

    Identifying hsp70 binding to the II-III loop and dissecting NK1-receptor tripartite modulation clarified how scaffold and G-protein signaling converge on the cytosolic loop.

    Evidence FLAG-tagged loop immunopurification with PKC autophosphorylation assay; Gβγ/Gαq buffering and pharmacology in HEK cells

    PMID:16543726 PMID:17050807

    Open questions at the time
    • hsp70 interaction is a single Co-IP/pulldown without reciprocal in vivo validation
    • Functional consequence of hsp70 binding on channel gating untested
  7. 2007 High

    S6 hydrophobic-residue scanning and knockout seizure studies linked channel gating chemistry to closed-state stability and established CaV2.3 in ictogenesis and excitotoxicity.

    Evidence Glycine-scanning mutagenesis with electrophysiology and modeling; CaV2.3 KO mice in kainate/NMDA seizure models with EEG and histology

    PMID:17376845 PMID:17660294

    Open questions at the time
    • Cell-type and circuit basis of seizure resistance not delineated
    • Link between S6 gating and excitotoxic Ca2+ load not directly tested
  8. 2011 High

    Knockout and slice work placed CaV2.3 at the core of reticular-thalamic oscillatory bursting and absence epilepsy, and a Sema3A/cGMP/PKG pathway showed CaV2.3 drives neurite identity conversion.

    Evidence CaV2.3 KO slice electrophysiology with SNX-482 and GBL absence model; Xenopus interneuron cultures with siRNA, PKG inhibitors, and live imaging

    PMID:21482359 PMID:21602796

    Open questions at the time
    • Mechanism linking CaV2.3 to slow AHP not fully resolved
    • How CaV2.3 instructs dendrite identity downstream undefined
  9. 2012 High

    Defining the CaVβ3 GK-domain leucine quartet as a determinant of CaV2.3 surface density established a structural basis for trafficking control.

    Evidence GK-domain mutagenesis with surface biotinylation and electrophysiology in heterologous cells

    PMID:22846999

    Open questions at the time
    • Trafficking machinery downstream of β binding unidentified
    • Relevance in native neurons untested
  10. 2014 High

    CaV2.3 was shown to drive sperm acrosome exocytosis under GM1/sterol control and to be inhibited via GABABR/c-Src phosphorylation of C-terminal tyrosines Y1761/Y1765, expanding its regulatory and physiological scope.

    Evidence KO mice, sperm Ca2+ imaging and AE assays, oocyte voltage clamp, lipid manipulation; tyrosine mutagenesis with c-Src manipulation and pertussis toxin in HEK cells

    PMID:24525187 PMID:24688019

    Open questions at the time
    • Direct molecular contact of GM1 with channel not resolved
    • In vivo neuronal role of GABABR/c-Src pathway untested
  11. 2017 Medium

    Identifying miR-34c-5p as a 3'UTR-targeting repressor of CaV2.3 in DRG neurons added post-transcriptional control and an antinociceptive role in peripheral sensory neurons.

    Evidence Luciferase 3'UTR reporter, in vivo DRG knockdown, cancer pain model, cultured DRG neurons

    PMID:28614186

    Open questions at the time
    • Single lab; direct endogenous miRNA-target occupancy not shown
    • Mechanism of channel-dependent hypersensitivity unresolved
  12. 2019 High

    Knockout neuroprotection and reciprocal NCS-1 regulation implicated CaV2.3 in dopaminergic neuron vulnerability, and FMRP binding/repression of CaV2.3 mRNA tied the channel to translational control relieved by group I mGluRs.

    Evidence CaV2.3 and NCS-1 KO mice, neurotoxin PD model, Ca2+ imaging, iPSC model; FMRP-mRNA binding in synaptoneurosomes, KO Western blot, R-type current recordings with mGluR pharmacology

    PMID:31350260 PMID:31704946

    Open questions at the time
    • Causal chain from Ca2+ load to degeneration not fully resolved
    • FMRP regulatory site on CaV2.3 mRNA not mapped
  13. 2021 High

    KCTD8/KCTD12b were identified as direct CaV2.3 binders at presynaptic active zones, and a NTSR2/CaV2.3 axis was shown to mediate contulakin-G spinal antinociception, defining presynaptic regulatory partners and an analgesic pathway.

    Evidence Co-IP, electrophysiology, active-zone co-localization, KCTD KO mice; CRISPR/Cas9 NTSR2 editing, DRG and spinal cord electrophysiology, synaptic fractionation

    PMID:33913808 PMID:35050960

    Open questions at the time
    • Structural basis of KCTD-CaV2.3 binding undefined
    • Direct vs indirect NTSR2-CaV2.3 coupling not fully resolved
  14. 2022 High

    Demonstrating that β2a/β2e splice variants stabilize CaV2.3 gating during pacemaking explained how the channel sustains current in repetitively firing dopaminergic neurons.

    Evidence tsA-201 expression with β2 splice variants, simulated-pacemaking patch-clamp, native SN neuron recordings with SNX-482, RT-PCR

    PMID:35792082

    Open questions at the time
    • Quantitative contribution of each β2 variant in vivo unclear
    • Link to degeneration phenotype not directly tested
  15. 2023 High

    Identifying CaV2.3 as a CDKL5 phosphorylation substrate whose dephosphorylation produces channel gain-of-function mechanistically connected CDKL5 deficiency disorder and CACNA1E gain-of-function epileptic encephalopathy.

    Evidence SILAC phosphoproteomics, recombinant channel electrophysiology, phosphomutant knock-in mice with excitability measurements

    PMID:38081835

    Open questions at the time
    • Precise phosphosite consequences on gating structure not resolved
    • Therapeutic implications untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many regulatory inputs (kinases, G-proteins, auxiliary subunits, RNA-binding/miRNA control) are integrated to set CaV2.3 function in each native cell type, and the structural basis of pathogenic gain-of-function, remain unresolved.
  • No high-resolution structure of full CaV2.3 complex in the corpus
  • Cell-type-specific combinatorial regulation not mapped
  • Mechanistic basis of DEE69 mutations beyond CDKL5 link undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-5653656 Vesicle-mediated transport 2
Partners
CACNB3CDKL5FMR1HSPA8KCTD12BKCTD8NCS1

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 The CaV2.3 (BII/α1E) channel is a high-voltage-activated calcium channel with unique Ni2+ sensitivity: its decaying current component shows high Ni2+ sensitivity similar to low-voltage-activated channels, while the sustained component is relatively resistant. It is insensitive to dihydropyridines, ω-CgTx-GVIA, and ω-Aga-IVA. Coexpression with the β subunit decelerates both activation and inactivation rates (opposite to L-type), and further coexpression of α2 subunit cancels this β effect. Xenopus oocyte expression, whole-cell electrophysiology, pharmacological profiling, auxiliary subunit co-expression Receptors & channels High 7719708
2001 Voltage-dependent inactivation of CaV2.3 is controlled by position R378 (position 5 of the AID motif) in the I-II linker: substitution with negatively charged residues (Glu or Asp) slows inactivation kinetics and shifts voltage dependence of inactivation to more positive voltages, while positively charged residues promote inactivation. This residue plays a significant role in inactivation gating. Site-directed mutagenesis, whole-cell patch-clamp electrophysiology in Xenopus oocytes Biophysical journal High 11159396
2004 PKC-mediated stimulation of CaV2.3 requires an arginine-rich region in the cytosolic II-III loop: phorbol ester activation of PKC augments CaV2.3 Ba2+ currents (~60%) and increases non-inactivating fraction (~3-fold), but this modulation is abolished when the arginine-rich region of the II-III loop is eliminated. This represents a positive feedback mechanism linking Ca2+ influx through other channels to CaV2.3 activation via PKC. Site-directed mutagenesis of II-III loop, whole-cell patch-clamp in HEK-293 cells, PKC inhibitor pharmacology The European journal of neuroscience High 15147300
2004 The C-terminal residues Trp13 and Ile14 of the AID helix in the I-II linker of CaV2.3 anchor CaVβ subunit functional modulation: Ile14 mutations to charged residues (Asp, Glu, Arg, Lys) abolish CaVβ3 binding and modulation, while I14L preserves modulation. A hydrophobic pocket at position 14 accounts for the strict structural specificity of the CaVβ interaction. Alanine-scanning and site-directed mutagenesis, [35S]CaVβ overlay binding assay, whole-cell electrophysiology in HEK cells, 3D homology modeling The Journal of biological chemistry High 15507442
2004 Muscarinic M1, M3, and M5 receptors (Gαq/11-coupled) stimulate CaV2.3 through a pathway involving Gαq/11, diacylglycerol, and a Ca2+-independent PKC (specifically blocked by neutralizing anti-Gαq/11 antibodies, PKCδ regulatory domain, phorbol ester pre-activation, or bisindolylmaleimide I). Muscarinic inhibition of CaV2.3 is mediated by Gβγ subunits, and PKC-mediated stimulation cross-talks with Gβγ-mediated inhibition. Heterologous expression in HEK cells, whole-cell patch-clamp, pharmacological inhibitors, neutralizing antibodies, co-expression of signaling pathway components Molecular pharmacology High 14742680
2005 CaV2.3 channels specifically control second-phase insulin release from pancreatic beta cells: CaV2.3 knockout or pharmacological block with SNX-482 suppresses second-phase secretion while leaving first-phase unaffected. CaV2.3 ablation also reduces oscillatory Ca2+ signaling and granule recruitment after the initial exocytotic burst. CaV2.3 knockout mice, dynamic insulin release measurements, pharmacological block with SNX-482, single beta cell Ca2+ imaging, capacitance measurements The Journal of clinical investigation High 15630454
2006 The molecular chaperone hsp70 interacts with the cytosolic II-III loop of CaV2.3 and may act as an adaptor for Ca2+-dependent targeting of PKC to E-type channels. Immunopurified II-III loop protein stimulates PKCα autophosphorylation. FLAG-tagged II-III loop overexpression in HEK 293 cells, immunopurification, identification of hsp70 as interaction partner, PKC autophosphorylation assay Cellular physiology and biochemistry Medium 16543726
2007 Hydrophobic residues in the IVS6 transmembrane segment of CaV2.3 (specifically the VAVIM motif) control the relative stability of the channel closed and open states: glycine substitutions at positions equivalent to Val1720 (in IS6, IIS6, IIIS6, and IVS6) produce slow inactivating currents with hyperpolarizing activation shifts, indicating that hydrophobic residues at these positions promote the channel closed state. Glycine-scanning mutagenesis of IVS6 (and equivalent positions in IS6, IIS6, IIIS6), whole-cell patch-clamp in heterologous expression, 3D homology modeling based on Kv1.2 The Journal of biological chemistry High 17660294
2007 CaV2.3 channels play a critical role in hippocampal ictogenesis and neuronal degeneration after excitotoxic events: CaV2.3-deficient mice show dramatic resistance to kainic acid-induced limbic seizures and absence of excitotoxic cell death in hippocampus after kainate, while wild-type mice exhibit clear excitotoxic neurodegeneration. CaV2.3 knockout mice, kainic acid and NMDA seizure models, surface and deep telemetric EEG recordings, histochemical analysis of hippocampal excitotoxicity Journal of neurophysiology High 17376845
2008 Eugenol inhibits CaV2.3 calcium channel currents in a TRPV1-independent manner, demonstrating a distinct mechanism from capsaicin (which requires TRPV1 for CaV2.3 inhibition). Whole-cell patch-clamp in E52 cell line stably expressing human CaV2.3, comparison between TRPV1-expressing and naïve cells Journal of dental research Medium 18218839
2011 CaV2.3 channels are critical for oscillatory burst discharges in reticular thalamus neurons and for absence epilepsy: in CaV2.3-/- mice, low-threshold spike bursts occur but subsequent oscillatory bursts are severely suppressed, with reduced slow afterhyperpolarization (AHP). Local blockade of CaV2.3 in the RT mimics the knockout phenotype. CaV2.3 knockout mice, brain slice electrophysiology, local pharmacological block with SNX-482, GBL-induced absence epilepsy model Neuron High 21482359
2011 Semaphorin 3A (Sema3A) induces axon-to-dendrite identity conversion in Xenopus spinal commissural interneurons by activating CaV2.3 channels: Sema3A triggers cGMP production and PKG activity that respectively induce CaV2.3 expression and dendrite identity acquisition. Inhibition of CaV2.3 results in multiple axon-like neurites. Cultured Xenopus spinal commissural interneuron experiments, pharmacological inhibition of CaV2.3, siRNA-mediated knockdown, PKG inhibitors, live imaging of neurite identity Nature cell biology High 21602796
2012 A quartet of leucine residues (L200, L303, L337, L342) in the guanylate kinase (GK) domain of CaVβ3 forms a hydrophobic pocket that determines CaV2.3 plasma membrane density: the quadruple mutant L200G/L303G/L337G/L342G nearly abolishes CaV2.3 cell surface density. Site-directed mutagenesis of CaVβ3 GK domain, surface biotinylation, whole-cell electrophysiology in heterologous expression system The Journal of biological chemistry High 22846999
2014 GM1 ganglioside and sterol efflux regulate acrosome exocytosis (AE) in sperm through CaV2.3 (α1E subunit): sperm lacking CaV2.3 show altered Ca2+ responses and reduced AE. AE depends on spatiotemporal information encoded by CaV2.3 flux. The GM1/CaV2.3 regulatory interaction requires GM1's lipid and sugar components and CaV2.3's α1E and α2δ subunits (defined by voltage clamp in Xenopus oocytes). CaV2.3 knockout mice, sperm Ca2+ imaging, acrosome exocytosis assays, Xenopus oocyte voltage clamp, lipid manipulation experiments Developmental cell High 24525187
2014 GABABR-mediated inhibition of CaV2.3 by cyclized Vc1.1 (c-Vc1.1) requires tyrosines 1761 and 1765 within exon 37 of the CaV2.3 C-terminus and is dependent on c-Src kinase phosphorylation at these sites. The inhibition is voltage-independent and pertussis toxin-sensitive, while baclofen inhibits CaV2.3 (~40%) via voltage-independent pathways. Overexpression of c-Src increases Vc1.1 inhibition; catalytically inactive c-Src abolishes it. Site-directed mutagenesis of CaV2.3 (Y1761, Y1765), heterologous expression in HEK cells, whole-cell patch-clamp, c-Src overexpression/dominant-negative, pertussis toxin, GABABR antagonist CGP55845 The Journal of general physiology High 24688019
2006 NK1 receptors modulate CaV2.3 through three distinct mechanisms: fast Gβγ-mediated inhibition, slow Gαq/11-mediated inhibition, and slow PKC-mediated stimulation. NK1 receptor activation also accelerates CaV2.3 inactivation kinetics. These pathways are dissectable by buffering Gβγ (transducin, GRK C-terminus) or Gαq/11 (RGS3T, PLCβ1 C-terminus). Heterologous expression in HEK 293 cells, whole-cell patch-clamp, co-expression of Gβγ/Gαq buffers, PKC inhibitor pharmacology Molecular pharmacology High 17050807
2019 CaV2.3 channels contribute to dopaminergic neuron loss in Parkinson's disease: CaV2.3 is more abundantly expressed in substantia nigra than ventral tegmental area neurons, its transcript is upregulated during aging, and CaV2.3 knockout provides full protection from degeneration in a neurotoxin PD mouse model. CaV2.3 deficiency reduces activity-associated somatic Ca2+ signals and Ca2+-dependent afterhyperpolarizations. CaV2.3 and NCS-1 show reciprocal regulation (Cav2.3 KO upregulates NCS-1; NCS-1 KO downregulates CaV2.3 and exacerbates neurodegeneration). CaV2.3 knockout mice, neurotoxin PD model (in vivo), somatic Ca2+ imaging, patch-clamp recordings, NCS-1 knockout mice, iPSC model of familial PD, quantitative PCR, Western blot Nature communications High 31704946
2019 FMRP binds the mRNA of CaV2.3 in mouse brain synaptoneurosomes and represses CaV2.3 translation under basal conditions. In FMRP KO hippocampal neurons, CaV2.3 protein is enhanced and R-type currents are abnormally large. Group I mGluR stimulation triggers CaV2.3 translation in an FMRP-dependent manner. Synaptoneurosomes mRNA binding (FMRP-CaV2.3 mRNA interaction), Western blot of CaV2.3 protein in FMRP KO neurons, whole-cell voltage-clamp of R-type currents, mGluR pharmacology The Journal of neuroscience High 31350260
2021 KCTD8 and KCTD12b (auxiliary GABABR subunits) directly bind to CaV2.3 in heterologous cells. KCTD8 potentiates CaV2.3 currents independent of GABABR activation. In rostral IPN, KCTD8, KCTD12b, and CaV2.3 co-localize at presynaptic active zones. Genetic deletion indicates bidirectional modulation of CaV2.3-mediated release by these KCTDs. Co-immunoprecipitation in heterologous cells, patch-clamp electrophysiology, immunofluorescence co-localization at presynaptic active zones, KCTD knockout mice eLife High 33913808
2021 Contulakin-G (CGX) produces spinal antinociception via a neurotensin receptor 2 (NTSR2)/CaV2.3 pathway: CRISPR/Cas9 editing and pharmacological block of NTSR2 reversed CGX antinociception, and electrophysiological and gene editing approaches showed CGX inhibition is dependent on CaV2.3 in sensory neurons. NTSR2 and CaV2.3 co-express in DRG neurons with predominantly presynaptic localization. CRISPR/Cas9 editing of NTSR2, intrathecal CGX delivery, electrophysiology of DRG neurons, synaptic fractionation, spinal cord slice electrophysiology, co-localization by anatomical studies Pain High 35050960
2022 β2a and β2e membrane-anchored splice variants of the β2 subunit stabilize CaV2.3 gating properties during simulated pacemaking, allowing sustained CaV2.3 availability and enhanced Ca2+ currents during bursts. β2a and β2e transcripts are expressed in mouse SN and identified SN dopaminergic neurons, and SNX-482-sensitive R-type currents in these neurons show voltage-dependent gating properties consistent with β2a/β2e modulation. tsA-201 cell expression with β2 splice variants, patch-clamp recordings during simulated pacemaking, patch-clamp of mouse DA midbrain neurons and SN brain slices, SNX-482 pharmacology, RT-PCR eLife High 35792082
2023 CDKL5 kinase phosphorylates CaV2.3 as a physiological substrate in mice and humans (identified by SILAC-based phosphoproteomics). Loss of CaV2.3 phosphorylation (phosphomutant mice) leads to channel gain-of-function via slower inactivation and enhanced cholinergic stimulation, resulting in increased neuronal excitability. This links CDKL5 deficiency disorder (CDD/DEE2) and CACNA1E gain-of-function DEE69 as mechanistically related channelopathies. SILAC-based phosphoproteomic screen for CDKL5 substrates, recombinant channel electrophysiology, Cav2.3 phosphomutant knock-in mice characterization, neuronal excitability measurements Nature communications High 38081835
2004 CaV2.3 (α1E) is present in embryonic mouse heart and is required for regular cardiac rhythmicity in prenatal hearts: CaV2.3-deficient embryonic hearts show >4-fold increased coefficient of variation in beating frequency (arrhythmia) compared to controls. SNX-482 (R-type blocker) induces arrhythmia in wild-type hearts, confirming that CaV2.3-containing channels stabilize regular prenatal heartbeat. Multielectrode array recordings of isolated embryonic hearts from CaV2.3-/- and wild-type mice (E9.5–E12.5), SNX-482 pharmacology Cellular physiology and biochemistry Medium 14976402
2017 miR-34c-5p negatively regulates CaV2.3 expression in dorsal root ganglion neurons: canonical and reciprocal regulation of miR-34c-5p and Cav2.3 was observed in cultured sensory neurons and in vivo in cancer pain models, and luciferase reporter assays confirmed functional binding of miR-34c-5p to the 3' UTR of Cav2.3 transcripts. Knockdown of Cav2.3 in DRG neurons causes hypersensitivity, indicating an antinociceptive role in peripheral sensory neurons. Luciferase 3'UTR reporter assay, in vivo DRG-specific Cav2.3 knockdown, cancer pain mouse model, cultured DRG neurons Pain Medium 28614186

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Optimization of the CHARMM additive force field for DNA: Improved treatment of the BI/BII conformational equilibrium. Journal of chemical theory and computation 445 22368531
1998 SR-BII, an isoform of the scavenger receptor BI containing an alternate cytoplasmic tail, mediates lipid transfer between high density lipoprotein and cells. The Journal of biological chemistry 196 9614139
1991 Purification and interaction properties of the human RNA polymerase B(II) general transcription factor BTF2. The Journal of biological chemistry 173 1939143
2005 CaV2.3 calcium channels control second-phase insulin release. The Journal of clinical investigation 152 15630454
2000 CaV2.2 and CaV2.3 (N- and R-type) Ca2+ channels in depolarization-evoked entry of Ca2+ into mouse sperm. The Journal of biological chemistry 138 10791962
1993 BI-BII transitions in B-DNA. Nucleic acids research 119 8441668
1976 Two forms of RNA polymerase B in yeast. Proteolytic conversion in vitro of enzyme BI into BII. European journal of biochemistry 97 780108
1976 Structural studies on yeast RNA polymerases. Existence of common subunits in RNA polymerases A(I) and B(II). The Journal of biological chemistry 86 767338
2006 Quantification of DNA BI/BII backbone states in solution. Implications for DNA overall structure and recognition. Journal of the American Chemical Society 83 16834390
2004 High density lipoprotein uptake by scavenger receptor SR-BII. The Journal of biological chemistry 83 14726519
2004 Electrophysiological and molecular evidence of L-(Cav1), N- (Cav2.2), and R- (Cav2.3) type Ca2+ channels in rat cortical astrocytes. Glia 78 14966867
2011 Galectin-1-expressing stromal cells constitute a specific niche for pre-BII cell development in mouse bone marrow. Blood 76 21511956
2004 DNA fine structure and dynamics in crystals and in solution: the impact of BI/BII backbone conformations. Biopolymers 72 14755572
2001 Screening of environmental contaminants for ecdysteroid agonist and antagonist activity using the Drosophila melanogaster B(II) cell in vitro assay. Environmental toxicology and chemistry 72 11521832
1994 Distinctive functional properties of the neuronal BII (class E) calcium channel. Receptors & channels 72 7719708
2011 Cav2.3 channels are critical for oscillatory burst discharges in the reticular thalamus and absence epilepsy. Neuron 71 21482359
2002 Human retinal pigment epithelial cells express scavenger receptors BI and BII. Biochemical and biophysical research communications 71 11944916
2000 BII nucleotides in the B and C forms of natural-sequence polymeric DNA: A new model for the C form of DNA. Journal of molecular biology 70 11099379
2019 Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson's disease. Nature communications 69 31704946
2007 The Cav2.3 calcium channel antagonist SNX-482 reduces dorsal horn neuronal responses in a rat model of chronic neuropathic pain. The European journal of neuroscience 66 17610575
2009 Impaired B-cell development at the pre-BII-cell stage in galectin-1-deficient mice due to inefficient pre-BII/stromal cell interactions. Blood 65 19329777
2009 Timosaponin B-II inhibits pro-inflammatory cytokine induction by lipopolysaccharide in BV2 cells. Archives of pharmacal research 62 19784587
2014 Lipid modulation of calcium flux through CaV2.3 regulates acrosome exocytosis and fertilization. Developmental cell 57 24525187
2016 Human SR-BI and SR-BII Potentiate Lipopolysaccharide-Induced Inflammation and Acute Liver and Kidney Injury in Mice. Journal of immunology (Baltimore, Md. : 1950) 53 26936883
2005 High density lipoprotein endocytosis by scavenger receptor SR-BII is clathrin-dependent and requires a carboxyl-terminal dileucine motif. The Journal of biological chemistry 53 16368683
1998 Solution structure of a non-palindromic 16 base-pair DNA related to the HIV-1 kappa B site: evidence for BI-BII equilibrium inducing a global dynamic curvature of the duplex. Journal of molecular biology 53 9636705
2007 Hippocampal seizure resistance and reduced neuronal excitotoxicity in mice lacking the Cav2.3 E/R-type voltage-gated calcium channel. Journal of neurophysiology 52 17376845
2007 Timosaponin B-II improves memory and learning dysfunction induced by cerebral ischemia in rats. Neuroscience letters 51 17566650
2001 Molecular determinants of inactivation within the I-II linker of alpha1E (CaV2.3) calcium channels. Biophysical journal 51 11159396
1996 The transition of pre-BI to pre-BII cells is dependent on the VH structure of the mu/surrogate L chain receptor. The EMBO journal 50 8612575
1983 Amino acid sequences of trypsin-chymotrypsin inhibitors (A-I, A-II, B-I, and B-II) from peanut (Arachis hypogaea): a discussion on the molecular evolution of legume Bowman-Birk type inhibitors. Journal of biochemistry 50 6630176
2021 Timosaponin BII improved osteoporosis caused by hyperglycemia through promoting autophagy of osteoblasts via suppressing the mTOR/NFκB signaling pathway. Free radical biology & medicine 46 33992678
1996 Solution structure of the CpG containing d(CTTCGAAG)2 oligonucleotide: NMR data and energy calculations are compatible with a BI/BII equilibrium at CpG. Biochemistry 44 8823193
2018 Proteomic analysis of olfactory bulb suggests CACNA1E as a promoter of CREB signaling in microbiota-induced depression. Journal of proteomics 42 30521978
2006 Amplification and overexpression of CACNA1E correlates with relapse in favorable histology Wilms' tumors. Clinical cancer research : an official journal of the American Association for Cancer Research 40 17189400
2008 A rapid and sensitive liquid chromatography-tandem mass spectrometric method for the determination of timosaponin B-II in blood plasma and a study of the pharmacokinetics of saponin in the rat. Journal of pharmaceutical and biomedical analysis 38 19027255
1984 Genetic organization of the polymorphic equine alpha globin locus and sequence of the BII alpha 1 gene. Nucleic acids research 38 6093055
2016 Timosaponin B-II Ameliorates Palmitate-Induced Insulin Resistance and Inflammation via IRS-1/PI3K/Akt and IKK/NF-[Formula: see text]B Pathways. The American journal of Chinese medicine 37 27222060
2014 Differential Cav2.1 and Cav2.3 channel inhibition by baclofen and α-conotoxin Vc1.1 via GABAB receptor activation. The Journal of general physiology 37 24688019
2011 Semaphorin 3A induces CaV2.3 channel-dependent conversion of axons to dendrites. Nature cell biology 37 21602796
2008 Modulation of CaV2.3 calcium channel currents by eugenol. Journal of dental research 37 18218839
2004 Human scavenger receptor class B type II (SR-BII) and cellular cholesterol efflux. The Biochemical journal 36 14570588
2000 8-Substituted cAMP analogues reveal marked differences in adaptability, hydrogen bonding, and charge accommodation between homologous binding sites (AI/AII and BI/BII) in cAMP kinase I and II. Biochemistry 36 10913291
2018 (C6H13N)2BiI5: A One-Dimensional Lead-Free Perovskite-Derivative Photoconductive Light Absorber. Inorganic chemistry 35 29608059
2001 17beta-Estradiol promotes the up-regulation of SR-BII in HepG2 cells and in rat livers. Journal of lipid research 35 11518764
2005 CaV2.3 channel and PKClambda: new players in insulin secretion. The Journal of clinical investigation 34 15630435
2020 Multisystem combined uranium resistance mechanisms and bioremediation potential of Stenotrophomonas bentonitica BII-R7: Transcriptomics and microscopic study. Journal of hazardous materials 33 33264934
2004 Arrhythmia in isolated prenatal hearts after ablation of the Cav2.3 (alpha1E) subunit of voltage-gated Ca2+ channels. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 33 14976402
2019 Reversal of Peripheral Neuropathic Pain by the Small-Molecule Natural Product Physalin F via Block of CaV2.3 (R-Type) and CaV2.2 (N-Type) Voltage-Gated Calcium Channels. ACS chemical neuroscience 32 30946560
2001 Assessment of natural products in the Drosophila melanogaster B(II) cell bioassay for ecdysteroid agonist and antagonist activities. Cellular and molecular life sciences : CMLS 32 11289314
2005 Sequence preference for BI/BII conformations in DNA: MD and crystal structure data analysis. Journal of biomolecular structure & dynamics 31 15918673
2017 miR-34c-5p functions as pronociceptive microRNA in cancer pain by targeting Cav2.3 containing calcium channels. Pain 30 28614186
2015 Timosaponin B-II ameliorates diabetic nephropathy via TXNIP, mTOR, and NF-κB signaling pathways in alloxan-induced mice. Drug design, development and therapy 30 26664046
2007 Polymorphisms in the gene encoding the voltage-dependent Ca(2+) channel Ca (V)2.3 (CACNA1E) are associated with type 2 diabetes and impaired insulin secretion. Diabetologia 29 17934712
2017 Influence of BII Backbone Substates on DNA Twist: A Unified View and Comparison of Simulation and Experiment for All 136 Distinct Tetranucleotide Sequences. Journal of chemical information and modeling 28 28059516
2013 Comparative pharmacokinetics of timosaponin B-II and timosaponin A-III after oral administration of Zhimu-Baihe herb-pair, Zhimu extract, free timosaponin B-II and free timosaponin A-III to rats. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 26 23542670
2009 Contribution of the intrinsic mechanical energy of the phosphodiester linkage to the relative stability of the A, BI, and BII forms of duplex DNA. The journal of physical chemistry. B 26 19708270
2005 Both the pre-BCR and the IL-7Ralpha are essential for expansion at the pre-BII cell stage in vivo. European journal of immunology 26 15909309
2004 Differential modulation of CaV2.3 Ca2+ channels by Galphaq/11-coupled muscarinic receptors. Molecular pharmacology 26 14742680
2015 Differential Deformability of the DNA Minor Groove and Altered BI/BII Backbone Conformational Equilibrium by the Monovalent Ions Li(+), Na(+), K(+), and Rb(+) via Water-Mediated Hydrogen Bonding. Journal of chemical theory and computation 25 26575937
2014 The effect and underlying mechanism of Timosaponin B-II on RGC-5 necroptosis induced by hydrogen peroxide. BMC complementary and alternative medicine 25 25439561
2006 Acetylcholine release at neuromuscular junctions of adult tottering mice is controlled by N-(cav2.2) and R-type (cav2.3) but not L-type (cav1.2) Ca2+ channels. The Journal of pharmacology and experimental therapeutics 25 16982704
2015 Timosaponin B-II inhibits lipopolysaccharide-induced acute lung toxicity via TLR/NF-κB pathway. Toxicology mechanisms and methods 24 26540118
2004 The cytosolic II-III loop of Cav2.3 provides an essential determinant for the phorbol ester-mediated stimulation of E-type Ca2+ channel activity. The European journal of neuroscience 24 15147300
1999 Helix morphology changes in B-DNA induced by spontaneous B(I)<==>B(II) substrate interconversion. Journal of biomolecular structure & dynamics 24 10563572
2014 The CaV2.3 R-type voltage-gated Ca2+ channel in mouse sleep architecture. Sleep 23 24790266
2004 The C-terminal residues in the alpha-interacting domain (AID) helix anchor CaV beta subunit interaction and modulation of CaV2.3 channels. The Journal of biological chemistry 23 15507442
2023 Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability. Nature communications 22 38081835
2021 GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals. eLife 21 33913808
2012 Timosaponin-BII inhibits the up-regulation of BACE1 induced by ferric chloride in rat retina. BMC complementary and alternative medicine 21 23082924
2007 The role of distal S6 hydrophobic residues in the voltage-dependent gating of CaV2.3 channels. The Journal of biological chemistry 21 17660294
2006 The molecular chaperone hsp70 interacts with the cytosolic II-III loop of the Cav2.3 E-type voltage-gated Ca2+ channel. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 21 16543726
2003 Localization of the calcium channel subunits Cav1.2 (alpha1C) and Cav2.3 (alpha1E) in the mouse organ of Corti. Histology and histopathology 21 12973680
1999 Four of five RAG-expressing JCkappa-/- small pre-BII cells have no L chain gene rearrangements: detection by high-efficiency single cell PCR. Immunity 21 10514009
2012 CACNA1E variants affect beta cell function in patients with newly diagnosed type 2 diabetes. the Verona newly diagnosed type 2 diabetes study (VNDS) 3. PloS one 20 22427875
2012 Metabolism profile of timosaponin B-II in urine after oral administration to rats by ultrahigh-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry. Rapid communications in mass spectrometry : RCM 20 22847693
2005 Compensatory contribution of Cav2.3 channels to acetylcholine release at the neuromuscular junction of tottering mice. Journal of neurophysiology 20 16381801
2002 The role of the phosphorus BI-BII transition in protein-DNA recognition: the NF-kappaB complex. Nucleic acids research 20 12384592
2023 Timosaponin BII inhibits TGF-β mediated epithelial-mesenchymal transition through Smad-dependent pathway during pulmonary fibrosis. Phytotherapy research : PTR 19 36807664
2017 Human SR-BII mediates SAA uptake and contributes to SAA pro-inflammatory signaling in vitro and in vivo. PloS one 19 28423002
1997 Biological activity of natural and synthetic ecdysteroids in the BII bioassay. Archives of insect biochemistry and physiology 19 9131786
2022 Mutations and clinical significance of calcium voltage-gated channel subunit alpha 1E (CACNA1E) in non-small cell lung cancer. Cell calcium 18 35026540
2006 Neurokinin 1 receptors trigger overlapping stimulation and inhibition of CaV2.3 (R-type) calcium channels. Molecular pharmacology 18 17050807
1999 Unexpected BII conformer substate population in unoriented hydrated films of the d(CGCGAATTCGCG)2 dodecamer and of native B-DNA from salmon testes. Biophysical journal 18 10388766
1981 Structure and action of heteronemertine polypeptide toxins. Amino acid sequence of Cerebratulus lacteus toxin B-II and revised structure of toxin B-IV. The Journal of biological chemistry 18 7263698
2021 Conotoxin contulakin-G engages a neurotensin receptor 2/R-type calcium channel (Cav2.3) pathway to mediate spinal antinociception. Pain 17 35050960
2018 Protective effects of timosaponin BII on oxidative stress damage in PC12 cells based on metabolomics. Biomedical chromatography : BMC 17 29920723
2016 The Role of Unconventional Hydrogen Bonds in Determining BII Propensities in B-DNA. The journal of physical chemistry letters 17 27935717
2011 Atropine-sensitive hippocampal θ oscillations are mediated by Cav2.3 R-type Ca²⁺ channels. Neuroscience 17 22240250
2020 Cav2.3 R-type calcium channels: from its discovery to pathogenic de novo CACNA1E variants: a historical perspective. Pflugers Archiv : European journal of physiology 16 32529299
2019 Disruption of GpI mGluR-Dependent Cav2.3 Translation in a Mouse Model of Fragile X Syndrome. The Journal of neuroscience : the official journal of the Society for Neuroscience 16 31350260
2022 Timosaponin B-II alleviates osteoarthritis-related inflammation and extracellular matrix degradation through inhibition of mitogen-activated protein kinases and nuclear factor-κB pathways in vitro. Bioengineered 15 35094658
2022 β2-subunit alternative splicing stabilizes Cav2.3 Ca2+ channel activity during continuous midbrain dopamine neuron-like activity. eLife 15 35792082
2021 De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures. Molecular autism 15 34702355
2017 Possible Involvement of the CACNA1E Gene in Migraine: A Search for Single Nucleotide Polymorphism in Different Clinical Phenotypes. Headache 15 28573794
2016 Opposite Associations Between the rs3845446 Single-Nucleotide Polymorphism of the CACNA1E Gene and Postoperative Pain-Related Phenotypes in Gastrointestinal Surgery Versus Previously Reported Orthognathic Surgery. The journal of pain 15 27480382
2014 Simultaneous determination of timosaponin B-II and A-III in rat plasma by LC-MS/MS and its application to pharmacokinetic study. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 14 25016164
2012 A quartet of leucine residues in the guanylate kinase domain of CaVβ determines the plasma membrane density of the CaV2.3 channel. The Journal of biological chemistry 14 22846999
2000 Resveratrol-type oligostilbenes from Iris clarkei antagonize 20-hydroxyecdysone action in the Drosophila melanogaster B(II) cell line. Cellular and molecular life sciences : CMLS 14 10766027
2013 How "Pharmacoresistant" is Cav2.3, the Major Component of Voltage-Gated R-type Ca2+ Channels? Pharmaceuticals (Basel, Switzerland) 13 24276260

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