Affinage

CACNA2D1

Voltage-dependent calcium channel subunit alpha-2/delta-1 · UniProt P54289

Length
1103 aa
Mass
124.6 kDa
Annotated
2026-04-28
99 papers in source corpus 44 papers cited in narrative 44 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CACNA2D1 (α2δ-1) is an auxiliary subunit of voltage-gated calcium channels that also functions as an independent signaling scaffold for glutamate receptors, governing excitatory synapse formation, synaptic strength, and nociceptive processing. As a calcium channel subunit, α2δ-1 promotes plasma membrane trafficking and modulates gating kinetics of CaV1.2 and CaV2 channels in neurons, smooth muscle, cardiac muscle, and pancreatic β-cells, with its N-terminal R-domain sufficient for trafficking and current enhancement (PMID:10534405, PMID:15536090, PMID:17563358, PMID:19797702, PMID:25966687). Independent of its channel role, α2δ-1 serves as the postsynaptic thrombospondin receptor that drives Rac1-dependent excitatory synaptogenesis and as a physical interaction partner of NMDARs and AMPARs: its C-terminal domain promotes PKC-dependent surface trafficking of NMDARs and disrupts GluA1/GluA2 heteromeric assembly while driving ubiquitin-proteasome degradation of GluA3, thereby increasing synaptic Ca²⁺-permeable AMPARs—mechanisms central to neuropathic pain, hypertension, ischemic injury, and synaptic plasticity (PMID:19818485, PMID:30054448, PMID:29490268, PMID:34252035, PMID:34289359, PMID:41129242). Biallelic loss-of-function variants in CACNA2D1 cause developmental epileptic encephalopathy (PMID:35293990). α2δ-1 is the obligate binding target of gabapentinoids (gabapentin/pregabalin), whose therapeutic effects in pain, anxiety, and synaptogenesis depend on disrupting α2δ-1-mediated receptor trafficking rather than direct calcium channel inhibition (PMID:21464332, PMID:21558437, PMID:29490268).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1999 High

    Establishing α2δ-1 as a potent enhancer of voltage-gated calcium channel currents resolved the question of whether this accessory subunit was functionally significant: co-expression with CaV2.1/β4 increased Q-type current density 18-fold.

    Evidence Reconstitution in HEK293 cells with whole-cell patch-clamp electrophysiology

    PMID:10534405

    Open questions at the time
    • Mechanism of current enhancement (trafficking vs. gating vs. both) was not resolved
    • Tissue-specific roles unknown
  2. 2004 High

    Two studies dissected tissue-specific contributions: in skeletal muscle α2δ-1 determines L-type current kinetics without affecting channel targeting, while in DRG neurons presynaptic α2δ-1 upregulation after nerve injury causally drives neuropathic allodynia, establishing α2δ-1 as a pain target.

    Evidence siRNA in dysgenic myotubes with patch-clamp; dorsal rhizotomy, intrathecal antisense, and behavioral nociception assays in rats

    PMID:15456823 PMID:15536090

    Open questions at the time
    • Whether α2δ-1 acts solely through CaV channels in pain was untested
    • Mechanism linking α2δ-1 upregulation to allodynia at the synaptic level was unclear
  3. 2007 High

    In cardiac muscle, α2δ-1 depletion shifted CaV1.2 voltage dependence and slowed kinetics without altering membrane targeting, demonstrating that α2δ-1's trafficking versus gating contributions are tissue-dependent.

    Evidence siRNA knockdown in dysgenic cells reconstituted with CaV1.2, patch-clamp, computational modeling

    PMID:17563358

    Open questions at the time
    • No in vivo cardiac phenotype confirmed
    • Whether effects apply to native cardiomyocytes was unverified
  4. 2009 High

    Three discoveries established α2δ-1 as both the thrombospondin receptor for excitatory synaptogenesis and a trafficking-dependent drug target: α2δ-1's VWF-A domain binds thrombospondins to drive postsynaptic synapse formation; α2δ-1 is required for CaV1.2 surface expression in cerebral artery myocytes controlling myogenic tone; and pregabalin exerts its antiallodynic effect by impairing anterograde α2δ-1 trafficking.

    Evidence Co-IP/domain mutagenesis/in vivo overexpression (synaptogenesis); shRNA/surface biotinylation/pressure myography (vascular); EM localization/in vivo chronic pregabalin (trafficking)

    PMID:19339603 PMID:19797702 PMID:19818485

    Open questions at the time
    • Pre- vs. postsynaptic requirement for synaptogenesis not yet dissected
    • Downstream signaling pathway from thrombospondin-α2δ-1 unknown
    • Whether gabapentinoid effects involve non-CaV targets was untested
  5. 2011 High

    Genetic proof that gabapentinoid pharmacology acts exclusively through α2δ-1: R217A knock-in mice lost pregabalin's effects on glutamate release and anxiolytic behavior, while α2δ-2 R279A mice retained anxiolytic responses, establishing isoform specificity. Concurrently, α2δ-1 was shown to target CaV channels to lipid rafts through protein-protein interactions independent of its GPI anchor.

    Evidence R217A and R279A knock-in mice with behavioral and glutamate release assays; chimeric constructs with sucrose gradient fractionation and electrophysiology

    PMID:21464332 PMID:21558437 PMID:21695204

    Open questions at the time
    • Whether lipid raft targeting is functionally required for gabapentinoid action was unknown
    • Whether non-CaV interactions contribute to gabapentinoid efficacy was untested
  6. 2013 High

    Global α2δ-1 knockout confirmed its requirement for normal calcium channel density and nociception: KO mice had reduced CaV2.2 in synaptosomes, diminished DRG calcium currents, and lost pregabalin's antiallodynic effect, while a splice variant with reduced gabapentin affinity was identified in neuropathic DRG neurons.

    Evidence α2δ-1 global KO with electrophysiology, synaptosome fractionation, behavioral assays; RT-PCR/radioligand binding for splice variant

    PMID:24133248 PMID:24315988

    Open questions at the time
    • KO effects on non-CaV synaptic functions not yet explored
    • Splice variant's in vivo significance for gabapentinoid resistance untested
  7. 2014 High

    Structure-function and interaction studies refined the mechanism: gabapentin reduces CaV2.2 surface expression through wild-type but not binding-insensitive α2δ-1, and the N-terminal R-domain was identified as the minimal region sufficient for both trafficking and current enhancement of CaV2.2.

    Evidence Exofacially tagged CaV2.2 with surface biotinylation and gabapentin-insensitive mutant; chimeric construct library with electrophysiology

    PMID:24889613 PMID:25966687

    Open questions at the time
    • Whether R-domain is also sufficient for non-CaV functions unknown
    • Structural basis for R-domain interaction with CaV unresolved
  8. 2015 High

    Functional consequences of α2δ-1 upregulation in DRG neurons were characterized: overexpression prolonged depolarization-evoked Ca²⁺ transients coupled to CaV2.2, with excess Ca²⁺ buffered by mitochondria, linking α2δ-1 to pathological calcium signaling.

    Evidence α2δ-1 overexpression in DRG neurons, Ca²⁺ imaging with ω-conotoxin GVIA and mitochondrial uptake inhibitors

    PMID:25878262

    Open questions at the time
    • Whether mitochondrial Ca²⁺ buffering contributes to neuropathic pain phenotype unknown
    • Link to synaptic transmission not tested
  9. 2017 High

    α2δ-1 overexpression alone was shown to be sufficient to increase excitatory synaptic connectivity and cause epileptiform activity in vivo, demonstrating that excess α2δ-1 drives network-level hyperexcitability beyond its known channel-trafficking role.

    Evidence Transgenic α2δ-1 overexpressing mice with mEPSC recording, VGluT2/PSD95 immunofluorescence, video-EEG

    PMID:28193459

    Open questions at the time
    • Whether epileptiform activity is CaV-dependent or synaptogenesis-dependent was untested
    • Relevance to human epilepsy unknown
  10. 2018 High

    A paradigm shift: α2δ-1 was identified as a physical interaction partner of NMDARs (via its C-terminus) that promotes NMDAR surface trafficking and synaptic targeting, operating independently of CaV channels. This α2δ-1–NMDAR complex was shown to mediate neuropathic pain, angiotensin II-induced sympathoexcitation, ischemic NMDAR hyperactivity, and corticostriatal LTP. Simultaneously, postsynaptic α2δ-1 was confirmed as the essential thrombospondin receptor signaling through Rac1 for synaptogenesis and spinogenesis.

    Evidence Reciprocal Co-IP in rodent/human tissue, Cacna2d1 KO, C-terminus interfering peptide, gabapentin, patch-clamp, infarct measurement, LTP recording, behavioral assays; conditional KO and autism-linked mutant rescue for synaptogenesis

    PMID:29490268 PMID:29971791 PMID:30054448 PMID:30104341 PMID:30355118 PMID:30355732 PMID:30431158

    Open questions at the time
    • Stoichiometry and structure of α2δ-1–NMDAR complex unresolved
    • Whether α2δ-1 directly contacts NMDAR subunits or uses adaptor proteins unknown
    • Neurexin–α2δ-1 interaction mechanism not fully defined
  11. 2020 High

    Calcineurin inhibition was identified as a signaling input that enhances α2δ-1–NMDAR coupling and synaptic trafficking in the spinal cord, with Cacna2d1 KO fully abolishing FK506-induced NMDAR hyperactivity, establishing α2δ-1 as a node regulated by phosphatase signaling.

    Evidence FK506 treatment, Co-IP, synaptosome fractionation, patch-clamp, Cacna2d1 KO, behavioral assays

    PMID:32269108

    Open questions at the time
    • Direct phosphorylation sites on α2δ-1 regulated by calcineurin not identified
    • Whether this mechanism generalizes beyond spinal cord untested
  12. 2021 High

    Two major advances defined α2δ-1's regulation of ionotropic glutamate receptor composition: PKC phosphorylation of GluN2A-S929/GluN2B-S1413 was identified as the mechanism by which α2δ-1 potentiates NMDAR co-trafficking to the surface, while α2δ-1 was shown to physically interact with GluA1 and GluA2 via its C-terminus to inhibit heteromeric AMPAR assembly and increase synaptic Ca²⁺-permeable AMPARs.

    Evidence HEK293 reconstitution with phosphoproteomics and site-directed mutagenesis; Co-IP, ER fractionation, rectification index and IEM-1460 sensitivity electrophysiology, C-terminus peptide disruption

    PMID:34252035 PMID:34289359

    Open questions at the time
    • Whether α2δ-1 directly catalyzes PKC-mediated phosphorylation or acts as scaffold unknown
    • Structural basis for α2δ-1 disruption of GluA1/GluA2 assembly unresolved
  13. 2022 High

    Transcriptional regulation of Cacna2d1 was resolved: HDAC2 constitutively represses the Cacna2d1 promoter, and nerve injury causes HDAC2 dissociation and histone hyperacetylation, explaining sustained α2δ-1 upregulation. Biallelic CACNA2D1 loss-of-function variants were shown to cause developmental epileptic encephalopathy, establishing the first Mendelian disease link. Additionally, α2δ-1–AMPAR interaction was extended to hypothalamic circuits driving hypertension, and α2δ-1–NMDAR coupling was implicated in opioid-induced synaptic plasticity.

    Evidence ChIP assay, conditional Hdac2 KO in DRG; patient fibroblasts with heterologous expression and electrophysiology; Co-IP in human hypothalamus with ER fractionation; morphine model with Cacna2d1 KO

    PMID:35038178 PMID:35293990 PMID:36222452 PMID:36257688

    Open questions at the time
    • Whether HDAC2-mediated regulation operates in non-DRG tissues unknown
    • Genotype-phenotype spectrum of CACNA2D1 mutations incomplete
    • Whether α2δ-1–AMPAR interaction in hypothalamus also involves GluA3 degradation untested
  14. 2023 High

    α2δ-1–NMDAR coupling was shown to be essential for calcineurin inhibitor-induced hypertension in hypothalamic presympathetic neurons, with Cacna2d1 KO fully preventing FK506-induced blood pressure elevation, while ΔFOSB was identified as an additional transcription factor directly activating Cacna2d1 expression.

    Evidence Co-IP, radiotelemetry, renal sympathetic nerve recording, Cacna2d1 KO; ChIP-qPCR with ΔFOSB knockdown/overexpression

    PMID:37167740 PMID:37605933

    Open questions at the time
    • Relative contributions of HDAC2 vs. ΔFOSB to Cacna2d1 transcription in different injury models unclear
    • Whether FK506-induced hypertension involves α2δ-1–AMPAR changes untested
  15. 2024 High

    The CK2–HDAC2–Cacna2d1 transcriptional axis was completed: CK2 phosphorylates HDAC2 at S394 after nerve injury, reducing HDAC2 occupancy at the Cacna2d1 promoter. CK2 and calcineurin were shown to reciprocally regulate α2δ-1–AMPAR interactions in spinal VGluT2 neurons, controlling CP-AMPAR levels.

    Evidence ChIP-qPCR, CK2 inhibitor CX-4945, phospho-specific Western, behavioral assays; cell-type specific electrophysiology with Co-IP and ER fractionation in VGluT2/VGAT neurons

    PMID:38886057 PMID:39357831

    Open questions at the time
    • Whether CK2 directly phosphorylates α2δ-1 itself is unknown
    • Full kinase/phosphatase network acting on α2δ-1 complexes not mapped
  16. 2025 High

    α2δ-1's mechanism for increasing CP-AMPARs was extended beyond GluA1/GluA2 disruption: α2δ-1 specifically promotes ubiquitin-proteasome degradation of GluA3 at K861, driving GluA1 homotetramer assembly, an isoform-specific effect (α2δ-1 but not α2δ-2/3). GABAergic/glycinergic disinhibition was shown to unleash α2δ-1-dependent NMDAR hyperactivity via mGluR5, placing α2δ-1 at the intersection of inhibitory tone and excitatory receptor trafficking.

    Evidence Ubiquitination assay with K861 mutagenesis, isoform comparison, intrathecal Gria3 gene delivery rescue; conditional Grin1 KO in DRG, Cacna2d1 KO, cell-type specific recordings, mGluR5 pharmacology

    PMID:41006062 PMID:41129242

    Open questions at the time
    • E3 ligase mediating GluA3 ubiquitination downstream of α2δ-1 not identified
    • Whether α2δ-1–mGluR5 interaction is direct or indirect unknown
    • No high-resolution structure of α2δ-1 in complex with any glutamate receptor

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of α2δ-1 interactions with NMDARs and AMPARs, whether α2δ-1 functions as a direct scaffold or recruits adaptor proteins, the identity of the E3 ubiquitin ligase mediating α2δ-1-dependent GluA3 degradation, and how CaV-dependent versus CaV-independent functions of α2δ-1 are differentially regulated in distinct cell types.
  • No atomic-resolution structure of α2δ-1 with any glutamate receptor complex
  • E3 ligase for GluA3 ubiquitination unknown
  • Relative in vivo contribution of CaV-dependent vs. CaV-independent α2δ-1 functions not separated in most disease models

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 4 GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 4
Localization
GO:0005886 plasma membrane 5 GO:0005783 endoplasmic reticulum 2 GO:0005829 cytosol 1
Pathway
R-HSA-112316 Neuronal System 8 R-HSA-382551 Transport of small molecules 6 R-HSA-9609507 Protein localization 5 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3
Partners
CACNA1BCACNA1CGRIA1GRIA2GRIA3GRIN1NRXN1THBS4
Complex memberships
Voltage-gated calcium channel (CaV1/CaV2)α2δ-1–AMPAR complexα2δ-1–NMDAR complex

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 α2δ-1 (CACNA2D1) is the neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. The VWF-A domain of α2δ-1 interacts with EGF-like repeats common to all thrombospondins. α2δ-1 overexpression increases synaptogenesis in vitro and in vivo, and is required postsynaptically for thrombospondin- and astrocyte-induced excitatory synapse formation. Gabapentin antagonizes thrombospondin binding to α2δ-1 and inhibits excitatory synapse formation. Co-IP, domain mutagenesis (VWF-A), overexpression in vitro and in vivo, loss-of-function, gabapentin competition assay Cell High 19818485
2009 Pregabalin reduces plasma membrane expression of α2δ-1 without affecting endocytosis, and its antiallodynic effect in neuropathic pain is associated with impaired anterograde trafficking of α2δ-1 to presynaptic terminals in the spinal cord, reducing neurotransmitter release. In vivo rat spinal nerve ligation model, light and electron microscopy of α2δ-1 distribution, in vitro surface expression assay, chronic pregabalin treatment The Journal of neuroscience High 19339603
2004 Spinal dorsal horn α2δ-1 upregulation after nerve injury derives from increased DRG α2δ-1, occurs presynaptically, and causally contributes to neuropathic allodynia. Dorsal rhizotomy and intrathecal antisense oligonucleotides blocking α2δ-1 both reversed tactile allodynia. Dorsal rhizotomy, intrathecal antisense oligonucleotides, immunohistochemistry, behavioral nociception assays The Journal of neuroscience High 15456823
2018 α2δ-1 forms a heteromeric complex with NMDARs in rodent and human spinal cords. The α2δ-1-NMDAR interaction occurs predominantly through the C terminus of α2δ-1 and promotes surface trafficking and synaptic targeting of NMDARs. Gabapentin or an α2δ-1 C-terminus-interfering peptide normalizes NMDAR synaptic targeting and activity increased by nerve injury, reducing pain hypersensitivity. Co-immunoprecipitation, overexpression, knockdown, knockout mice, electrophysiology (patch-clamp), C-terminus interfering peptide, behavioral assays Cell reports High 29490268
2018 Postsynaptic but not presynaptic α2δ-1 is required and sufficient for TSP-induced synaptogenesis in vitro and spine formation in vivo. TSP-α2δ-1 interactions control synaptogenesis postsynaptically via Rac1. An α2δ-1 mutant linked to autism cannot rescue these synaptogenesis defects. Global or cell-specific loss of α2δ-1 yields profound deficits in excitatory synapse numbers and spinogenesis in mouse cortex. Cell-specific conditional KO, in vitro synaptogenesis assay, in vivo spine counting, Rac1 pathway analysis, autism-linked mutant rescue The Journal of cell biology High 30054448
2014 α2δ-1 is tightly associated with CaV2.2 at the plasma membrane; α2δ-1 increases plasma-membrane CaV2.2 expression. Gabapentin reduces CaV2.2 cell-surface expression in the presence of wild-type α2δ-1 (but not a gabapentin-insensitive α2δ-1 mutant) without disrupting the CaV2.2-α2δ-1 interaction. Exofacially tagged functional CaV2.2 constructs, antigen retrieval, immunofluorescence, surface biotinylation, patch-clamp electrophysiology Proceedings of the National Academy of Sciences of the United States of America High 24889613
2013 α2δ-1 knockout mice show reduced calcium channel current density in DRG neurons, reduced CaV2.2 levels in brain and spinal cord synaptosomes, lower mechanical and cold sensitivity, and delayed development of mechanical hypersensitivity after nerve injury. Pregabalin's antiallodynic effect is lost in α2δ-1 knockout mice. α2δ-1 global knockout mice, patch-clamp electrophysiology, synaptosome fractionation, in vivo electrophysiology of dorsal horn WDR neurons, behavioral assays, TRPM8 agonist response The Journal of neuroscience High 24133248
2004 In skeletal muscle, α2δ-1 is the major determinant of characteristic slow L-type Ca2+ current kinetics but is not essential for targeting of CaV1.2 channels to triads or for excitation-contraction coupling. siRNA silencing of α2δ-1 accelerates current kinetics without affecting Ca2+ current amplitude or voltage-dependence. siRNA knockdown in dysgenic myotubes and BC3H1 cells, immunofluorescence, whole-cell patch-clamp, Ca2+ transient measurements The Journal of biological chemistry High 15536090
2009 α2δ-1 is essential for plasma membrane expression of arterial myocyte CaV1.2 α1 subunits in cerebral artery smooth muscle cells. α2δ-1 knockdown reduces surface CaV1.2, decreases intracellular Ca2+, inhibits pressure-induced vasoconstriction (myogenic tone), and attenuates pregabalin-induced vasodilation. shRNA knockdown, surface biotinylation, whole-cell patch-clamp, pressure myography, Ca2+ imaging Circulation research High 19797702
2007 In cardiac muscle, α2δ-1 depletion does not perturb membrane expression or targeting of CaV1.2, but shifts voltage dependence of Ca2+ current activation by +9 mV and slows activation/inactivation kinetics ~2-fold. Computer modeling predicts this causes 60% prolongation of action potential and 2-fold increase in Ca2+ concentration per contraction. siRNA knockdown in dysgenic muscle cells reconstituted with CaV1.2, patch-clamp, computational modeling of ventricular myocytes Proceedings of the National Academy of Sciences of the United States of America High 17563358
2011 Gabapentin and pregabalin attenuate stimulus-evoked glutamate release in rat neocortical slices via the α2δ-1 subunit of voltage-sensitive Ca2+ channels. PGB had no effect on glutamate release in transgenic mice with a gabapentin-insensitive point mutation (R217A) of α2δ-1. Enzyme-based microelectrode array measurement of glutamate, transgenic R217A knock-in mice, pharmacological competition with L-isoleucine The Journal of pharmacology and experimental therapeutics High 21464332
2011 The anxiolytic-like effects of pregabalin are mediated specifically by binding to the α2δ-1 subunit (not α2δ-2). Pregabalin was inactive in α2δ-1 R217A point mutant mice but active in α2δ-2 R279A mutant mice in the Vogel conflict test. α2δ-1 R217A and α2δ-2 R279A knock-in mouse strains, Vogel conflict test behavioral assay The Journal of pharmacology and experimental therapeutics High 21558437
2012 α2δ-1 is targeted to lipid rafts independently of a GPI-anchoring motif; upstream residues govern lipid raft targeting via protein-protein rather than lipid-lipid interactions. Truncated α2δ-1 lacking its C-terminal membrane anchor can still enhance calcium channel currents, demonstrating that membrane anchoring is not strictly required for current enhancement. Chimeric construct expression, sucrose gradient fractionation (lipid raft isolation), electrophysiology, PI-PLC treatment The Journal of biological chemistry Medium 22869375
2011 Lipid raft association of α2δ-1 is independent of its GPI-anchoring motif; upstream sequences are required for raft targeting and likely mediate protein-protein interactions. α2δ-1 is required for targeting CaV channels to lipid rafts. GPI-motif chimera expression, sucrose density gradient fractionation, electrophysiology, PI-PLC treatment PloS one Medium 21695204
2015 Upregulation of α2δ-1 in sensory DRG neurons leads to prolonged Ca2+ responses evoked by depolarization, coupled to CaV2.2 channel-mediated responses, with the prolonged Ca2+ transients buffered by mitochondria preferentially activated by Ca2+ influx through CaV2.2 channels. Overexpression in rat DRG neurons, Ca2+ imaging, ω-conotoxin GVIA pharmacology, mitochondrial Ca2+ uptake inhibitor, removal of extracellular Ca2+ The Journal of neuroscience High 25878262
2013 A splice variant of α2δ-1 (ΔA+BΔC) is differentially upregulated in small nonmyelinated DRG neurons after spinal nerve ligation, supports CaV2 calcium currents with unaltered properties, but shows significantly reduced affinity for gabapentin compared to the main splice variant. RT-PCR splice variant identification, density gradient DRG neuron separation, patch-clamp electrophysiology, radioligand binding affinity assay Pain Medium 24315988
2016 Thrombospondin-4 partially co-immunoprecipitates with α2δ-1 intracellularly, reducing gabapentin binding affinity to α2δ-1 in a Mg2+-dependent manner through the VWF-A domain. However, no association was detected between thrombospondin-4 and α2δ-1 on the cell surface. Co-immunoprecipitation, [3H]-gabapentin radioligand binding assay, VWF-A domain mutants, cell surface assay Scientific reports Medium 27076051
2018 α-Neurexin 1α (Nrxn1α) acts as a positive regulator of Ca2+ influx through CaV2.1 channels containing α2δ-1 subunits but not α2δ-3, without altering channel kinetics. In αNrxn triple KO neurons, α2δ-1 has elevated surface mobility on axons, and Nrxn1α coexpression with α2δ-1 facilitates Ca2+ currents of recombinant CaV2.1. αNrxn triple KO neurons, Ca2+ indicator live imaging, whole-cell patch-clamp of recombinant CaV2.1, vesicle release assays, synaptic protein quantification The Journal of neuroscience High 30104341
2018 α2δ-1 forms a complex with NMDARs in the hypothalamus of rodents and humans. Angiotensin II (Ang II) via AT1 receptors increases the prevalence of synaptic α2δ-1-NMDAR complexes, potentiating presynaptic and postsynaptic NMDAR activity; these effects are abolished by pregabalin or an α2δ-1 C-terminus interfering peptide, or in Cacna2d1 KO mice. Co-immunoprecipitation (rodent and human tissue), patch-clamp electrophysiology, Cacna2d1 KO mice, C-terminus peptide, sympathoexcitatory response assay The Journal of neuroscience High 29921713
2018 α2δ-1-NMDAR complexes in the hypothalamic PVN are required for potentiated presynaptic and postsynaptic NMDAR activity of presympathetic neurons and for elevated sympathetic outflow in spontaneously hypertensive rats. α2δ-1 protein and α2δ-1-NMDAR complexes are upregulated in synaptosomes of hypertensive rats. Co-immunoprecipitation, synaptosome fractionation, patch-clamp electrophysiology, gabapentin treatment, C-terminus peptide, in vivo sympathetic nerve recording, arterial blood pressure telemetry The Journal of physiology High 29971791
2018 Brain ischemia rapidly enhances the α2δ-1-NMDAR physical interaction and increases α2δ-1 protein glycosylation. α2δ-1-bound NMDARs mediate ischemia-induced NMDAR hyperactivity; inhibiting α2δ-1, disrupting α2δ-1-NMDAR interaction, or Cacna2d1 KO abolishes OGD-induced NMDAR hyperactivity and reduces infarct volumes and neurological deficits. Co-immunoprecipitation, Cacna2d1 KO mice, gabapentin pharmacology, C-terminus interfering peptide, patch-clamp in hippocampal neurons, infarct volume measurement, calpain/caspase-3 activity Stroke High 30355118
2018 α2δ-1-NMDAR coupling in the striatum is required for corticostriatal LTP. α2δ-1 physically interacts with NMDARs in striatum of mice and humans. Theta-burst stimulation-induced LTP is abolished by gabapentin, α2δ-1 C-terminus peptide, or Cacna2d1 KO, and is associated with α2δ-1-dependent NMDAR activity. Disrupting this interaction impairs learning and memory tasks. Co-immunoprecipitation (rodent and human), field and patch-clamp electrophysiology (LTP), Cacna2d1 KO, gabapentin, C-terminus peptide, behavioral assays (T-maze, rotarod) The Journal of biological chemistry High 30355732
2021 α2δ-1 coexpression significantly increases NMDAR activity (GluN1/GluN2A and GluN1/GluN2B) in HEK293 cells. PKC activation (PMA) increases the α2δ-1-GluN1 interaction and promotes co-trafficking to the cell surface; PKC inhibition abolishes α2δ-1-induced NMDAR potentiation. S929 on GluN2A and S1413 on GluN2B are the PKC phosphorylation sites responsible for NMDAR potentiation by PKC and α2δ-1. HEK293 transfection, patch-clamp electrophysiology, Co-immunoprecipitation, surface biotinylation, quantitative phosphoproteomics, site-directed mutagenesis, Cacna2d1 KO mice The Journal of neuroscience High 34252035
2021 α2δ-1 physically interacts with both GluA1 and GluA2 AMPA receptor subunits via its C terminus, inhibits GluA1/GluA2 heteromeric assembly, and increases GluA2 retention in the endoplasmic reticulum, thereby increasing GluA2-lacking Ca2+-permeable AMPA receptors (CP-AMPARs) at synapses. Gabapentin or an α2δ-1 C-terminus-disrupting peptide restores GluA1/GluA2 heteromeric assembly. Co-immunoprecipitation, surface and synaptosome fractionation, ER fractionation, patch-clamp (rectification index, IEM-1460 sensitivity), overexpression and KO, C-terminus peptide Cell reports High 34289359
2022 HDAC2 constitutively suppresses Cacna2d1 transcription by binding to its promoter in DRG neurons. Nerve injury causes HDAC2 dissociation from the Cacna2d1 promoter and histone hyperacetylation, leading to sustained α2δ-1 upregulation. Conditional Hdac2 KO in DRG neurons upregulates α2δ-1 and potentiates α2δ-1-dependent NMDAR activity, causing pain hypersensitivity reversed by gabapentin. ChIP assay, conditional DRG-specific Hdac2 KO, Cacna2d1 KO, Western blot, patch-clamp electrophysiology, behavioral pain assays The Journal of neuroscience High 36257688
2022 Biallelic loss-of-function variants in CACNA2D1 cause developmental epileptic encephalopathy. A missense variant (Gly209Asp) severely reduces α2δ-1G209D trafficking to the cell surface and completely abolishes its ability to increase CaV2 channel trafficking and function. Patient fibroblast analysis (nonsense-mediated decay), heterologous expression of α2δ-1G209D, surface expression assay, whole-cell patch-clamp of CaV2 channels Brain High 35293990
1999 CACNA2 (α2δ-1) enhances Q-type (CaV2.1/α1A) Ca2+ current density 18-fold when co-transfected with α1A and β4 subunits in HEK293 cells. The gene spans >150 kb with at least 40 exons (2 alternatively spliced). Genomic cloning, full-length cDNA construction, co-transfection in HEK293 cells, whole-cell patch-clamp electrophysiology Genomics High 10534405
2014 USP2-45 de-ubiquitylates both CaV1.2 and α2δ-1 subunits, and this interaction requires co-expression of α2δ-1. α2δ-1 (but not CaV1.2 or β2) co-precipitates with USP2-45, suggesting USP2-45 binds α2δ-1 to promote de-ubiquitylation of both subunits, which decreases surface expression of CaV1.2. Co-immunoprecipitation, whole-cell current recordings, surface biotinylation, co-transfection in tsA-201 and HEK-293 cells Pflugers Archiv Medium 25366495
2016 In α2δ-1 knockout DRG neurons, action potential duration is reduced and firing frequency in response to sustained depolarization is decreased, consistent with reduced Ca2+ entry per AP. This is associated with reduced Ca2+ buffering and is not mediated by BK or SK channel activation. α2δ-1 KO mice, patch-clamp action potential recordings in DRG neurons, Ca2+ imaging (proximal axon segment), pharmacological BK/SK channel blockade Philosophical transactions of the Royal Society of London. Series B, Biological sciences Medium 27377724
2015 The N-terminal 'R-domain' of α2δ-1 is the minimal region necessary and sufficient for its electrophysiological and trafficking effects on CaV2.2, identified by systematic chimeric construct mapping. Chimeric construct library (sequential N-terminal extensions in PIN-G reporter), patch-clamp electrophysiology, imaging Current molecular pharmacology Medium 25966687
2019 TCF7L2 regulates Cacna2d1 gene expression, and α2δ-1 suppression impairs CaV1.2 trafficking to the plasma membrane (accumulation in recycling endosomes), reducing voltage-gated Ca2+ currents and glucose-induced insulin secretion in pancreatic beta-cells. α2δ-1 overexpression rescued TCF7L2-silencing-induced Ca2+ signaling defects. Tcf7l2 and Cacna2d1 siRNA knockdown, α2δ-1 overexpression rescue, live Ca2+ imaging, whole-cell patch-clamp, insulin secretion assay, confocal imaging of channel trafficking Molecular and cellular endocrinology Medium 31805307
2018 Chronic paclitaxel treatment increases α2δ-1 expression and potentiates the α2δ-1-NMDAR interaction and synaptic trafficking in the spinal cord, leading to tonic activation of presynaptic NMDARs and pain hypersensitivity. Inhibiting α2δ-1 trafficking, disrupting α2δ-1-NMDAR interaction, or α2δ-1 genetic ablation reverses these effects. Co-immunoprecipitation, synaptosome fractionation, patch-clamp electrophysiology, Cacna2d1 KO, gabapentin, C-terminus interfering peptide, behavioral assays Journal of neurochemistry High 30431158
2020 Calcineurin inhibition (FK506) enhances the physical interaction between α2δ-1 and NMDARs and their synaptic trafficking, causing tonic activation of presynaptic and postsynaptic NMDARs in the spinal cord and pain hypersensitivity. α2δ-1 KO abolishes these FK506-induced effects. Co-immunoprecipitation, synaptosome fractionation, patch-clamp electrophysiology (mEPSCs, evoked EPSCs, puff NMDAR currents), Cacna2d1 KO, gabapentin, α2δ-1Tat peptide, behavioral assays The Journal of neuroscience High 32269108
2024 CK2 phosphorylates HDAC2 at serine-394, enhancing CK2-HDAC2 interaction in DRG after nerve injury and diminishing HDAC2 enrichment at the Cacna2d1 promoter, thereby promoting Cacna2d1 transcription. CK2 inhibition reverses nerve injury-induced α2δ-1 upregulation and pain hypersensitivity. Co-immunoprecipitation (CK2-HDAC2 interaction), ChIP-qPCR (HDAC2 and histone acetylation at Cacna2d1 promoter), CK2 inhibitor CX-4945, phospho-specific Western blot, behavioral pain assays The Journal of biological chemistry High 39357831
2025 α2δ-1 promotes GluA1 homotetramer assembly and synaptic CP-AMPAR expression by driving ubiquitin-proteasome-mediated degradation of GluA3. α2δ-1 coexpression increases GluA3 ubiquitination at K861 at the GluA3 C-terminus. This effect is isoform-specific (α2δ-1 but not α2δ-2 or α2δ-3). Intrathecal Gria3 gene delivery reverses neuropathic pain and CP-AMPARs by restoring GluA2/GluA3 heteromers. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K861), α2δ isoform comparison, proteasome inhibition, intrathecal gene delivery, patch-clamp electrophysiology, nerve injury model The Journal of clinical investigation High 41129242
2012 In hypertension, transcriptional upregulation of α2δ-1 in cerebral artery myocytes promotes surface trafficking of CaV1.2 channels, increasing CaV1.2 current density and reducing current inactivation, leading to vasoconstriction. Pregabalin normalizes α2δ-1 and CaV1.2 surface expression and vasoconstriction without altering total protein. Surface biotinylation, whole-cell patch-clamp, pressure myography, spontaneously hypertensive rat model, pregabalin treatment Hypertension Medium 22949532
2022 α2δ-1 promotes synaptic CP-AMPARs in the hypothalamic PVN in hypertension by inhibiting GluA1/GluA2 heteromeric assembly in the ER. α2δ-1 directly interacts with GluA1 and GluA2 in rodent and human hypothalamus; α2δ-1-AMPAR complex levels are elevated in SHR. C-terminus peptide disruption restores GluA1/GluA2 heteromers and normalizes CP-AMPAR-mediated EPSCs. Co-immunoprecipitation (rodent and human tissue), ER fractionation, patch-clamp electrophysiology (rectification, IEM-1460 sensitivity), gabapentin, C-terminus peptide Journal of neurochemistry High 35038178
2023 α2δ-1 is essential for calcineurin inhibitor (FK506)-induced synaptic NMDAR hyperactivity in hypothalamic PVN presympathetic neurons and subsequent hypertension development. FK506 increases α2δ-1-GluN1 complex levels in PVN synaptosomes; Cacna2d1 KO mice do not develop FK506-induced hypertension. Co-immunoprecipitation, synaptosome fractionation, patch-clamp (retrogradely labeled PVN neurons), radiotelemetry blood pressure recording, Cacna2d1 KO mice, gabapentin, C-terminus peptide, renal sympathetic nerve recording Circulation research High 37605933
2023 ΔFOSB transcription factor directly binds the Cacna2d1 gene promoter (confirmed by ChIP-qPCR), transcriptionally activating Cacna2d1 expression in mouse hippocampal neurons in response to cigarette smoke exposure, causing calcium overload. ChIP-qPCR, ΔFOSB knockdown and overexpression, calcium imaging, Ca2+ concentration measurement Ecotoxicology and environmental safety Medium 37167740
2017 Overexpression of α2δ-1 alone in transgenic mice increases cortical excitatory synaptic connectivity (increased mEPSC frequency/amplitude, increased VGluT2/PSD95 appositions) and leads to spontaneous epileptiform activity and behavioral arrests. Ethosuximide reversibly eliminated the epileptiform activity. Transgenic α2δ-1 overexpressing mice, whole-cell patch-clamp (mEPSCs, evoked EPSCs), field potential recordings, dual immunofluorescence (Vglut2/PSD95), video-EEG monitoring, ethosuximide treatment Neurobiology of disease High 28193459
2014 α2δ-1 signaling in the nucleus accumbens is necessary for cocaine-induced relapse. Gabapentin preferentially reduces amplitude and increases paired-pulse ratio of EPSCs in nucleus accumbens of cocaine-experienced rats, and microinjection of gabapentin into the NAc core attenuates cocaine-primed reinstatement. Cocaine self-administration and extinction model, whole-cell patch-clamp of EPSCs in NAc slices, intra-NAc gabapentin microinjection, locomotor assays, sucrose reinstatement control The Journal of neuroscience Medium 24948814
2022 Repeated opioid (morphine) exposure increases α2δ-1-GluN1 interaction and synaptic trafficking of NMDARs in the NAc. Cacna2d1 KO abolishes morphine-induced increase in NMDAR-mediated mEPSCs and puff NMDAR currents in NAc medium spiny neurons. α2δ-1 C-terminus peptide disruption and gabapentin replicate the KO phenotype. Co-immunoprecipitation, synaptosome fractionation, patch-clamp electrophysiology, Cacna2d1 KO, gabapentin, C-terminus peptide, conditioned place preference, locomotor sensitization Journal of neurochemistry High 36222452
2025 GABAergic and glycinergic inhibitory inputs tonically suppress α2δ-1-dependent presynaptic and postsynaptic NMDAR activity at primary afferent→excitatory neuron synapses in the spinal cord. Cacna2d1 KO abolishes disinhibition-induced NMDAR hyperactivity and nociceptive hypersensitivity. mGluR5 is also essential for disinhibition-induced NMDAR hyperactivity via α2δ-1. Conditional Grin1 KO in DRG neurons, Cacna2d1 KO, VGluT2/VGAT cell-type specific recordings, patch-clamp (mEPSCs, evoked EPSCs, puff NMDA currents), intrathecal drug delivery, mGluR5 pharmacology The Journal of neuroscience High 41006062
2024 Calcineurin and CK2 reciprocally regulate α2δ-1-mediated GluA1/GluA2 heteromeric assembly in spinal excitatory (VGluT2) neurons. Calcineurin inhibition (FK506) increases α2δ-1 interactions with GluA1 and GluA2 and reduces GluA1/GluA2 heteromers in the ER, promoting CP-AMPARs; CK2 inhibition reverses these effects and FK506-induced pain hypersensitivity. Co-immunoprecipitation, ER fractionation, patch-clamp (rectification, IEM-1460), cell-type specific (VGluT2/VGAT) recordings, Cacna2d1 KO, CK2 inhibitor, C-terminus peptide, behavioral assays The Journal of neuroscience High 38886057

Source papers

Stage 0 corpus · 99 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell 734 19818485
2009 The increased trafficking of the calcium channel subunit alpha2delta-1 to presynaptic terminals in neuropathic pain is inhibited by the alpha2delta ligand pregabalin. The Journal of neuroscience : the official journal of the Society for Neuroscience 351 19339603
2018 The α2δ-1-NMDA Receptor Complex Is Critically Involved in Neuropathic Pain Development and Gabapentin Therapeutic Actions. Cell reports 226 29490268
2004 Spinal dorsal horn calcium channel alpha2delta-1 subunit upregulation contributes to peripheral nerve injury-induced tactile allodynia. The Journal of neuroscience : the official journal of the Society for Neuroscience 201 15456823
2001 Dorsal root ganglion neurons show increased expression of the calcium channel alpha2delta-1 subunit following partial sciatic nerve injury. Brain research. Molecular brain research 177 11687271
2018 Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1. The Journal of cell biology 123 30054448
2014 Functional exofacially tagged N-type calcium channels elucidate the interaction with auxiliary α2δ-1 subunits. Proceedings of the National Academy of Sciences of the United States of America 112 24889613
2013 α2δ-1 gene deletion affects somatosensory neuron function and delays mechanical hypersensitivity in response to peripheral nerve damage. The Journal of neuroscience : the official journal of the Society for Neuroscience 101 24133248
2004 The Ca2+ channel alpha2delta-1 subunit determines Ca2+ current kinetics in skeletal muscle but not targeting of alpha1S or excitation-contraction coupling. The Journal of biological chemistry 74 15536090
2009 Smooth muscle cell alpha2delta-1 subunits are essential for vasoregulation by CaV1.2 channels. Circulation research 68 19797702
2018 Increased α2δ-1-NMDA receptor coupling potentiates glutamatergic input to spinal dorsal horn neurons in chemotherapy-induced neuropathic pain. Journal of neurochemistry 64 30431158
2018 α-Neurexins Together with α2δ-1 Auxiliary Subunits Regulate Ca2+ Influx through Cav2.1 Channels. The Journal of neuroscience : the official journal of the Society for Neuroscience 63 30104341
2018 Focal Cerebral Ischemia and Reperfusion Induce Brain Injury Through α2δ-1-Bound NMDA Receptors. Stroke 62 30355118
2014 Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability. European journal of human genetics : EJHG 57 25074461
2011 Amperometric measurement of glutamate release modulation by gabapentin and pregabalin in rat neocortical slices: role of voltage-sensitive Ca2+ α2δ-1 subunit. The Journal of pharmacology and experimental therapeutics 54 21464332
2021 Protein Kinase C-Mediated Phosphorylation and α2δ-1 Interdependently Regulate NMDA Receptor Trafficking and Activity. The Journal of neuroscience : the official journal of the Society for Neuroscience 47 34252035
2012 Transcriptional upregulation of α2δ-1 elevates arterial smooth muscle cell voltage-dependent Ca2+ channel surface expression and cerebrovascular constriction in genetic hypertension. Hypertension (Dallas, Tex. : 1979) 46 22949532
2007 Computer modeling of siRNA knockdown effects indicates an essential role of the Ca2+ channel alpha2delta-1 subunit in cardiac excitation-contraction coupling. Proceedings of the National Academy of Sciences of the United States of America 46 17563358
2019 α2δ-1-Bound N-Methyl-D-aspartate Receptors Mediate Morphine-induced Hyperalgesia and Analgesic Tolerance by Potentiating Glutamatergic Input in Rodents. Anesthesiology 45 30839350
2020 Calcineurin Inhibition Causes α2δ-1-Mediated Tonic Activation of Synaptic NMDA Receptors and Pain Hypersensitivity. The Journal of neuroscience : the official journal of the Society for Neuroscience 43 32269108
2018 The α2δ-1-NMDA receptor coupling is essential for corticostriatal long-term potentiation and is involved in learning and memory. The Journal of biological chemistry 43 30355732
2015 The upregulation of α2δ-1 subunit modulates activity-dependent Ca2+ signals in sensory neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 43 25878262
2021 α2δ-1 Upregulation in Primary Sensory Neurons Promotes NMDA Receptor-Mediated Glutamatergic Input in Resiniferatoxin-Induced Neuropathy. The Journal of neuroscience : the official journal of the Society for Neuroscience 41 34252037
2021 α2δ-1 switches the phenotype of synaptic AMPA receptors by physically disrupting heteromeric subunit assembly. Cell reports 41 34289359
2011 Anxiolytic-like activity of pregabalin in the Vogel conflict test in α2δ-1 (R217A) and α2δ-2 (R279A) mouse mutants. The Journal of pharmacology and experimental therapeutics 41 21558437
2018 α2δ-1 Is Essential for Sympathetic Output and NMDA Receptor Activity Potentiated by Angiotensin II in the Hypothalamus. The Journal of neuroscience : the official journal of the Society for Neuroscience 40 29921713
2018 α2δ-1 couples to NMDA receptors in the hypothalamus to sustain sympathetic vasomotor activity in hypertension. The Journal of physiology 37 29971791
2017 Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility. Nature communications 36 29176626
2013 Differential upregulation in DRG neurons of an α2δ-1 splice variant with a lower affinity for gabapentin after peripheral sensory nerve injury. Pain 36 24315988
2022 Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental epileptic encephalopathy. Brain : a journal of neurology 34 35293990
2016 Thrombospondin-4 reduces binding affinity of [(3)H]-gabapentin to calcium-channel α2δ-1-subunit but does not interact with α2δ-1 on the cell-surface when co-expressed. Scientific reports 34 27076051
2022 HDAC2 in Primary Sensory Neurons Constitutively Restrains Chronic Pain by Repressing α2δ-1 Expression and Associated NMDA Receptor Activity. The Journal of neuroscience : the official journal of the Society for Neuroscience 33 36257688
2012 Calcium currents are enhanced by α2δ-1 lacking its membrane anchor. The Journal of biological chemistry 33 22869375
2018 Calcium channel α2δ1 subunit (CACNA2D1) enhances radioresistance in cancer stem-like cells in non-small cell lung cancer cell lines. Cancer management and research 31 30464601
2017 Epileptiform activity and behavioral arrests in mice overexpressing the calcium channel subunit α2δ-1. Neurobiology of disease 29 28193459
2011 Targeting of voltage-gated calcium channel α2δ-1 subunit to lipid rafts is independent from a GPI-anchoring motif. PloS one 29 21695204
2024 Quercetin alleviates chronic unpredictable mild stress-induced depression-like behavior by inhibiting NMDAR1 with α2δ-1 in rats. CNS neuroscience & therapeutics 28 38615365
2021 α2δ-1-Dependent NMDA Receptor Activity in the Hypothalamus Is an Effector of Genetic-Environment Interactions That Drive Persistent Hypertension. The Journal of neuroscience : the official journal of the Society for Neuroscience 25 34193557
2014 Hypothalamic dysfunction of the thrombospondin receptor α2δ-1 underlies the overeating and obesity triggered by brain-derived neurotrophic factor deficiency. The Journal of neuroscience : the official journal of the Society for Neuroscience 24 24403154
2014 α2δ-1 signaling in nucleus accumbens is necessary for cocaine-induced relapse. The Journal of neuroscience : the official journal of the Society for Neuroscience 24 24948814
2014 Altered expression of the voltage-gated calcium channel subunit α₂δ-1: a comparison between two experimental models of epilepsy and a sensory nerve ligation model of neuropathic pain. Neuroscience 23 24641886
2022 Brief Opioid Exposure Paradoxically Augments Primary Afferent Input to Spinal Excitatory Neurons via α2δ-1-Dependent Presynaptic NMDA Receptors. The Journal of neuroscience : the official journal of the Society for Neuroscience 21 36379705
2020 MicroRNA-107 inhibits proliferation and invasion of laryngeal squamous cell carcinoma cells by targeting CACNA2D1 in vitro. Anti-cancer drugs 21 31725046
2016 Oxaliplatin administration increases expression of the voltage-dependent calcium channel α2δ-1 subunit in the rat spinal cord. Journal of pharmacological sciences 21 26883453
2014 miR‑107 promotes the erythroid differentiation of leukemia cells via the downregulation of Cacna2d1. Molecular medicine reports 20 25373460
2010 Novel SNPs of the bovine CACNA2D1 gene and their association with carcass and meat quality traits. Molecular biology reports 20 20585886
2023 Brain α2δ-1-Bound NMDA Receptors Drive Calcineurin Inhibitor-Induced Hypertension. Circulation research 19 37605933
2020 Effect and mechanism of the CACNA2D1-CGRP pathway in osteoarthritis-induced ongoing pain. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 19 32570114
2018 Peripheral nerve injury increases contribution of L-type calcium channels to synaptic transmission in spinal lamina II: Role of α2δ-1 subunits. Molecular pain 19 29580153
2017 α2δ-1 Signaling Drives Cell Death, Synaptogenesis, Circuit Reorganization, and Gabapentin-Mediated Neuroprotection in a Model of Insult-Induced Cortical Malformation. eNeuro 18 29109971
2016 Effect of knockout of α2δ-1 on action potentials in mouse sensory neurons. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 18 27377724
2014 Ubiquitin-specific protease USP2-45 acts as a molecular switch to promote α2δ-1-induced downregulation of Cav1.2 channels. Pflugers Archiv : European journal of physiology 18 25366495
1996 Anesthesiologic problems in Williams syndrome: the CACNL2A locus is not involved. Human genetics 18 8707301
2011 Single nucleotide polymorphism of CACNA2D1 gene and its association with milk somatic cell score in cattle. Molecular biology reports 17 21225462
2022 α2δ-1 protein promotes synaptic expression of Ca2+ permeable-AMPA receptors by inhibiting GluA1/GluA2 heteromeric assembly in the hypothalamus in hypertension. Journal of neurochemistry 16 35038178
2018 Pushing the Limits of Computational Structure-Based Drug Design with a Cryo-EM Structure: The Ca2+ Channel α2δ-1 Subunit as a Test Case. Journal of chemical information and modeling 16 30053380
2014 Mapping breakpoints of a familial chromosome insertion (18,7) (q22.1; q36.2q21.11) to DPP6 and CACNA2D1 genes in an azoospermic male. Gene 16 24937803
2010 Genetic polymorphisms of the CACNA2D1 gene and their association with carcass and meat quality traits in cattle. Biochemical genetics 16 20549332
1999 Genomic structure and functional expression of a human alpha(2)/delta calcium channel subunit gene (CACNA2). Genomics 16 10534405
2018 Candidate SNP of CACNA2D1 Gene Associated with Clinical Mastitis and Production Traits in Sahiwal (Bos taurus indicus) and Karan Fries (Bos taurus taurus × Bos taurus indicus). Animal biotechnology 14 29463160
2022 Functions and Clinical Significance of CACNA2D1 in Gastric Cancer. Annals of surgical oncology 13 35445337
2021 The α2δ-1/NMDA receptor complex is involved in brain injury after intracerebral hemorrhage in mice. Annals of clinical and translational neurology 13 34032393
2019 The TCF7L2-dependent high-voltage activated calcium channel subunit α2δ-1 controls calcium signaling in rodent pancreatic beta-cells. Molecular and cellular endocrinology 13 31805307
2025 α2δ-1-Linked NMDA and AMPA Receptors in Neuropathic Pain and Gabapentinoid Action. Journal of neurochemistry 12 40191897
2022 α2δ-1 protein drives opioid-induced conditioned reward and synaptic NMDA receptor hyperactivity in the nucleus accumbens. Journal of neurochemistry 12 36222452
2023 The α2δ-1-NMDA receptor complex and its potential as a therapeutic target for ischemic stroke. Frontiers in neurology 10 37153659
2021 Calcium Channel Subunit α2δ-1 as a Potential Biomarker Reflecting Illness Severity and Neuroinflammation in Patients with Acute Ischemic Stroke. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 10 34049015
2015 Upregulation of α₂δ-1 Calcium Channel Subunit in the Spinal Cord Contributes to Pelvic Organ Cross-Sensitization in a Rat Model of Experimentally-Induced Endometriosis. Neurochemical research 10 25935199
2014 The perfect storm? Histiocytoid cardiomyopathy and compound CACNA2D1 and RANGRF mutation in a baby. Cardiology in the young 9 24438356
1996 Influence of protein conditioning films on binding of a bacterial polysaccharide adhesin from Hyphomonas MHS-3. Biofouling 9 22115100
2024 Calcineurin and CK2 Reciprocally Regulate Synaptic AMPA Receptor Phenotypes via α2δ-1 in Spinal Excitatory Neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 8 38886057
2021 The α2δ-1-NMDAR1 interaction in the trigeminal ganglion contributes to orofacial ectopic pain following inferior alveolar nerve injury. Brain research bulletin 8 33811955
2022 Development of a PET radioligand for α2δ-1 subunit of calcium channels for imaging neuropathic pain. European journal of medicinal chemistry 7 36031695
2021 Aberrant Axo-Axonic Synaptic Reorganization in the Phosphorylated L1-CAM/Calcium Channel Subunit α2δ-1-Containing Central Terminals of Injured c-Fibers in the Spinal Cord of a Neuropathic Pain Model. eNeuro 7 33500315
2023 Cigarette smoke triggers calcium overload in mouse hippocampal neurons via the ΔFOSB-CACNA2D1 axis to impair cognitive performance. Ecotoxicology and environmental safety 6 37167740
2024 Exercise training affects calcium ion transport by downregulating the CACNA2D1 protein to reduce hypertension-induced myocardial injury in mice. iScience 5 38495825
2024 CACNA2D1 regulates the progression and influences the microenvironment of colon cancer. Journal of gastroenterology 5 38536483
2023 Cherry leaf decoction inhibits NMDAR expression and thereby ameliorates CUMS- induced depression-like behaviors through downregulation of α2δ-1. Heliyon 5 38034773
2022 The Novel Gabapentinoid Mirogabalin Prevents Upregulation of α2δ-1 Subunit of Voltage-Gated Calcium Channels in Spinal Dorsal Horn in a Rat Model of Spinal Nerve Ligation. Drug research 5 36216339
2015 The R-Domain: Identification of an N-terminal Region of the α2δ-1 Subunit Which is Necessary and Sufficient for its Effects on Cav2.2 Calcium Currents. Current molecular pharmacology 5 25966687
2020 Sex-specific Effects of α2δ-1 in the Ventromedial Hypothalamus of Female Mice Controlling Glucose and Lipid Balance. Endocrinology 4 32337532
2024 The role of voltage-gated calcium channel α2δ-1 in the occurrence and development in myofascial orofacial pain. BMC oral health 3 38735923
2024 Nerve injury augments Cacna2d1 transcription via CK2-mediated phosphorylation of the histone deacetylase HDAC2 in dorsal root ganglia. The Journal of biological chemistry 3 39357831
2022 Role of the Ca2+ channel α2δ-1 auxiliary subunit in proliferation and migration of human glioblastoma cells. PloS one 3 36520928
2025 Association of the CACNA2D1 gene with milk yield and milk quality traits in Holstein cattle. The Journal of dairy research 2 40383546
2025 AI-Driven Drug Target Screening Platform Identified Oncogene CACNA2D1 Activated by Enhancer Infestation in Epstein-Barr Virus-Associated Nasopharyngeal Carcinoma. International journal of molecular sciences 2 40429844
2025 Tonic GABA and Glycine Inhibition Control Pain Hypersensitivity via Limiting α2δ-1- and mGluR5-Dependent NMDA Receptor Activity at Primary Afferent→Excitatory Neuron Synapses. The Journal of neuroscience : the official journal of the Society for Neuroscience 2 41006062
2024 Towards Multitargeted Ligands as Pain Therapeutics: Dual Ligands of the Cavα2δ-1 Subunit of Voltage-Gated Calcium Channel and the μ-Opioid Receptor. ChemMedChem 2 38230842
2024 Influence of the calcium voltage-gated channel auxiliary subunit (CACNA2D1) absence on intraocular pressure in mice. Experimental eye research 1 38373629
2022 [A novel cell tool for α2δ-1-NMDAR target-based analgesic drug discovery]. Sheng wu gong cheng xue bao = Chinese journal of biotechnology 1 35355481
2020 [MicroRNA-107 inhibits the proliferation and invasion of laryngeal squamous cell carcinoma cells by targeting CACNA2D1]. Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology head and neck surgery 1 33254297
2017 Dominance effects estimation of TLR4 and CACNA2D1 genes for health and production traits using logistic regression. Journal of genetics 1 29321363
2026 Chaihu-Baishao confers antidepressant effects in CSDS mice by ameliorating hippocampal synaptic plasticity impairment via blocking α2δ-1-NR2B interaction. Journal of ethnopharmacology 0 41740819
2026 LncRNA 4930544M13Rik-201 regulates CACNA2D1 expression via interacting with hnRNPA2B1 to promote neuropathic pain following nerve injury. Brain research bulletin 0 41864512
2025 Unraveling the Role of α2δ-1 in Cerebral Hemorrhage: Calcium Overload, Endoplasmic Reticulum Stress, and Microglial Apoptosis. Brain and behavior 0 40329779
2025 Spinal α2δ-1 induces GluA3 degradation to regulate assembly of calcium-permeable AMPA receptors and pain hypersensitivity. The Journal of clinical investigation 0 41129242
2025 α2δ-1-NMDAR1 complex in the hypothalamic paraventricular nucleus mediates anxiety-induced sympathetic hyperactivity. Clinical autonomic research : official journal of the Clinical Autonomic Research Society 0 41219589
2024 Scavenger Receptor Class B Type I Modulates Epileptic Seizures and Receptor α2δ-1 Expression. Neurochemical research 0 39017956
2024 Novel heterozygous mutation of CACNA2D1 gene in a Chinese family with arrhythmia. BMC cardiovascular disorders 0 39354346