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Gene and Protein Information  |
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| Species | TM | P Loops | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 24 | 4 | 2161 | 3p21.1 | CACNA1D | calcium voltage-gated channel subunit alpha1 D | 35,61 |
| Mouse | 24 | 4 | 2179 | 14 B | Cacna1d | calcium channel, voltage-dependent, L type, alpha 1D subunit | 78 |
| Rat | 24 | 4 | 2203 | 16p16 | Cacna1d | calcium voltage-gated channel subunit alpha1 D | 30,79 |
| Previous and Unofficial Names |
| neuroendocrine L-type Ca2+ channel | α1D | CACH3 | CACN4 | CACNL1A2 | CCHL1A2 | calcium channel alpha-1 subunit | Cchl1a | calcium channel |
| Database Links |
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| Alphafold | Q01668 (Hs), Q99246 (Mm), P27732 (Rn) |
| ChEMBL Target | CHEMBL4138 (Hs), CHEMBL4132 (Rn) |
| DrugBank Target | Q01668 (Hs) |
| Ensembl Gene | ENSG00000157388 (Hs), ENSMUSG00000015968 (Mm), ENSRNOG00000013147 (Rn) |
| Entrez Gene | 776 (Hs), 12289 (Mm), 29716 (Rn) |
| Human Protein Atlas | ENSG00000157388 (Hs) |
| KEGG Gene | hsa:776 (Hs), mmu:12289 (Mm), rno:29716 (Rn) |
| OMIM | 114206 (Hs) |
| Orphanet | ORPHA327310 (Hs) |
| Pharos | Q01668 (Hs) |
| RefSeq Nucleotide | NM_000720 (Hs), NM_028981 (Mm), NM_017298 (Rn) |
| RefSeq Protein | NP_000711 (Hs), NP_083257 (Mm), NP_058994 (Rn) |
| UniProtKB | Q01668 (Hs), Q99246 (Mm), P27732 (Rn) |
| Wikipedia | CACNA1D (Hs) |
| Associated Proteins |
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| Functional Characteristics |
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| L-type calcium current: more negative activation voltage range than Cav1.2, calcium-dependent inactivation | |
| Ion Selectivity and Conductance |
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| Voltage Dependence |
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| Voltage Dependence Comments | ||||||||||||||||||||||
| Data are given for both Ca2+ and Ba2+ as the charge carrier. V0.5 for activation is higher with Ca2+ as a charge carrier than with Ba2+ (but more negative than for Cav1.2 under identical experimental conditions; [79]). Activation and inactivation parameters differ between different C-terminal splice variants (long and several short forms; [5,37,65,72]). Short forms lack a C-terminal modulatory domain which reduces calcium-dependent inactivation and reduces voltage-sensitivity. Inactivation time course depends on associated β subunit (slower with β2), C-terminal splice variant and on charge carrier (pronounced calcium-induced inactivation with Ca2+; [65]). |
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Download all structure-activity data for this target as a CSV file 
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| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Using rat channels, BAYK 8644 (1μM) shifted the V0.5 towards a more hyperpolarised voltage (-32.2mV to -39.0mV) [79]. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gating inhibitors
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| View species-specific gating inhibitor tables | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gating Inhibitor Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inhibition by dihydropyridines (e.g. isradipine [35,48]) is voltage-dependent with a higher apparent affinity at more depolarised voltage. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Channel Blockers | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| View species-specific channel blocker tables | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Channel Blocker Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Amlodopine, isradipine, nifedipine, nitrendipine, and nimodipineare examples of dihydropyridine calcium channel antagonists. Verapamil is a phenylalkylamine calcium channel blocker. Diltiazem is an example of a benzothiazepine calcium channel blocker. Cav1.3 is less sensitive to dihydropyridine antagonists than Cav1.2. The Cryo-EM structure of the human Cav1.3 channel bound to cinnarizine revealed a direct pore blockade by the drug [80]. Cinnarizine also inhibits cardiac Cav1.2 L-type and T-type channels with submicromolar Ki values but its subtype selectivity remains unclear [13]. At present there is no robust evidence for Cav1.3-selective calcium channel blockers [18]. |
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| Immunopharmacology Comments |
| Cav1.3 and Cav1.4 are involved in CD8+ T cell survival and cytokine production [47]. |
| Cell Type Associations | ||||
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| Tissue Distribution
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| Tissue Distribution Comments | ||||||||
| The physiological role of Cav1.3 L-type channels for lymphocyte function is not well established. Additionally, in lymphocytes the presence of Cav1.3 α1 subunit protein has not yet been proven using Cav1.3-α1 deficient mice as negative controls; therefore the specificity of antibody staining remians questionable [10,69]. | ||||||||
| Functional Assays
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| Physiological Functions
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| Physiological Consequences of Altering Gene Expression
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| Phenotypes, Alleles and Disease Models
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| Clinically-Relevant Mutations and Pathophysiology
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| Clinically-Relevant Mutations and Pathophysiology Comments | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gain of function is shown for the somatic mutations causing aldosterone-producing adrenal adenomas, and for the germline mutations causing Congenital Hyperinsulinemic Hypoglycemia, Neurodevelopmental Abnormalities with Autism, and PASNA (for review see reference [49]). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Biologically Significant Variants
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1. Arab SF, Düwel P, Jüngling E, Westhofen M, Lückhoff A. (2004) Inhibition of voltage-gated calcium currents in type II vestibular hair cells by cinnarizine. Naunyn Schmiedebergs Arch Pharmacol, 369 (6): 570-5. [PMID:15138660]
2. Azizan EA, Poulsen H, Tuluc P, Zhou J, Clausen MV, Lieb A, Maniero C, Garg S, Bochukova EG, Zhao W et al.. (2013) Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat Genet, 45 (9): 1055-60. [PMID:23913004]
3. Badou A, Jha MK, Matza D, Mehal WZ, Freichel M, Flockerzi V, Flavell RA. (2006) Critical role for the beta regulatory subunits of Cav channels in T lymphocyte function. Proc Natl Acad Sci USA, 103 (42): 15529-34. [PMID:17028169]
4. Baig SM, Koschak A, Lieb A, Gebhart M, Dafinger C, Nürnberg G, Ali A, Ahmad I, Sinnegger-Brauns MJ, Brandt N et al.. (2011) Loss of Ca(v)1.3 (CACNA1D) function in a human channelopathy with bradycardia and congenital deafness. Nat Neurosci, 14 (1): 77-84. [PMID:21131953]
5. Bock G, Gebhart M, Scharinger A, Jangsangthong W, Busquet P, Poggiani C, Sartori S, Mangoni ME, Sinnegger-Brauns MJ, Herzig S et al.. (2011) Functional properties of a newly identified C-terminal splice variant of Cav1.3 L-type Ca2+ channels. J Biol Chem, 286 (49): 42736-48. [PMID:21998310]
6. Brandt A, Khimich D, Moser T. (2005) Few CaV1.3 channels regulate the exocytosis of a synaptic vesicle at the hair cell ribbon synapse. J Neurosci, 25 (50): 11577-85. [PMID:16354915]
7. Brandt A, Striessnig J, Moser T. (2003) CaV1.3 channels are essential for development and presynaptic activity of cochlear inner hair cells. J Neurosci, 23 (34): 10832-40. [PMID:14645476]
8. Busquet P, Nguyen NK, Schmid E, Tanimoto N, Seeliger MW, Ben-Yosef T, Mizuno F, Akopian A, Striessnig J, Singewald N. (2010) CaV1.3 L-type Ca2+ channels modulate depression-like behaviour in mice independent of deaf phenotype. Int J Neuropsychopharmacol, 13 (4): 499-513. [PMID:19664321]
9. Béguin P, Nagashima K, Gonoi T, Shibasaki T, Takahashi K, Kashima Y, Ozaki N, Geering K, Iwanaga T, Seino S. (2001) Regulation of Ca2+ channel expression at the cell surface by the small G-protein kir/Gem. Nature, 411 (6838): 701-6. [PMID:11395774]
10. Cabral MD, Paulet PE, Robert V, Gomes B, Renoud ML, Savignac M, Leclerc C, Moreau M, Lair D, Langelot M et al.. (2010) Knocking down Cav1 calcium channels implicated in Th2 cell activation prevents experimental asthma. Am J Respir Crit Care Med, 181 (12): 1310-7. [PMID:20167851]
11. Calin-Jageman I, Yu K, Hall RA, Mei L, Lee A. (2007) Erbin enhances voltage-dependent facilitation of Ca(v)1.3 Ca2+ channels through relief of an autoinhibitory domain in the Ca(v)1.3 alpha1 subunit. J Neurosci, 27 (6): 1374-85. [PMID:17287512]
12. Clark NC, Nagano N, Kuenzi FM, Jarolimek W, Huber I, Walter D, Wietzorrek G, Boyce S, Kullmann DM, Striessnig J et al.. (2003) Neurological phenotype and synaptic function in mice lacking the CaV1.3 alpha subunit of neuronal L-type voltage-dependent Ca2+ channels. Neuroscience, 120 (2): 435-42. [PMID:12890513]
13. Cohen CJ, Spires S, Van Skiver D. (1992) Block of T-type Ca channels in guinea pig atrial cells by antiarrhythmic agents and Ca channel antagonists. J Gen Physiol, 100 (4): 703-28. [PMID:1281221]
14. Cui G, Meyer AC, Calin-Jageman I, Neef J, Haeseleer F, Moser T, Lee A. (2007) Ca2+-binding proteins tune Ca2+-feedback to Cav1.3 channels in mouse auditory hair cells. J Physiol (Lond.), 585 (Pt 3): 791-803. [PMID:17947313]
15. Cunha SR, Hund TJ, Hashemi S, Voigt N, Li N, Wright P, Koval O, Li J, Gudmundsson H, Gumina RJ et al.. (2011) Defects in ankyrin-based membrane protein targeting pathways underlie atrial fibrillation. Circulation, 124 (11): 1212-22. [PMID:21859974]
16. De Mingo Alemany MC, Mifsud Grau L, Moreno Macián F, Ferrer Lorente B, León Cariñena S. (2020) A de novo CACNA1D missense mutation in a patient with congenital hyperinsulinism, primary hyperaldosteronism and hypotonia. Channels (Austin), 14 (1): 175-180. [PMID:32336187]
17. Dick IE, Tadross MR, Liang H, Tay LH, Yang W, Yue DT. (2008) A modular switch for spatial Ca2+ selectivity in the calmodulin regulation of CaV channels. Nature, 451 (7180): 830-4. [PMID:18235447]
18. Filippini L, Ortner NJ, Kaserer T, Striessnig J. (2023) Cav 1.3-selective inhibitors of voltage-gated L-type Ca2+ channels: Fact or (still) fiction?. Br J Pharmacol, 180 (10): 1289-1303. [PMID:36788128]
19. Flanagan SE, Vairo F, Johnson MB, Caswell R, Laver TW, Lango Allen H, Hussain K, Ellard S. (2017) A CACNA1D mutation in a patient with persistent hyperinsulinaemic hypoglycaemia, heart defects, and severe hypotonia. Pediatr Diabetes, 18 (4): 320-323. [PMID:28318089]
20. Gebhart M, Juhasz-Vedres G, Zuccotti A, Brandt N, Engel J, Trockenbacher A, Kaur G, Obermair GJ, Knipper M, Koschak A et al.. (2010) Modulation of Cav1.3 Ca2+ channel gating by Rab3 interacting molecule. Mol Cell Neurosci, 44 (3): 246-59. [PMID:20363327]
21. Giordano TP, Tropea TF, Satpute SS, Sinnegger-Brauns MJ, Striessnig J, Kosofsky BE, Rajadhyaksha AM. (2010) Molecular switch from L-type Ca v 1.3 to Ca v 1.2 Ca2+ channel signaling underlies long-term psychostimulant-induced behavioral and molecular plasticity. J Neurosci, 30 (50): 17051-62. [PMID:21159975]
22. Grant L, Fuchs P. (2008) Calcium- and calmodulin-dependent inactivation of calcium channels in inner hair cells of the rat cochlea. J Neurophysiol, 99 (5): 2183-93. [PMID:18322004]
23. Gregory FD, Bryan KE, Pangršič T, Calin-Jageman IE, Moser T, Lee A. (2011) Harmonin inhibits presynaptic Cav1.3 Ca²⁺ channels in mouse inner hair cells. Nat Neurosci, 14 (9): 1109-11. [PMID:21822269]
24. Gregory FD, Pangrsic T, Calin-Jageman IE, Moser T, Lee A. (2013) Harmonin enhances voltage-dependent facilitation of Cav1.3 channels and synchronous exocytosis in mouse inner hair cells. J Physiol (Lond.), 591 (Pt 13): 3253-69. [PMID:23613530]
25. Helton TD, Xu W, Lipscombe D. (2005) Neuronal L-type calcium channels open quickly and are inhibited slowly. J Neurosci, 25 (44): 10247-51. [PMID:16267232]
26. Hibino H, Pironkova R, Onwumere O, Rousset M, Charnet P, Hudspeth AJ, Lesage F. (2003) Direct interaction with a nuclear protein and regulation of gene silencing by a variant of the Ca2+-channel beta 4 subunit. Proc Natl Acad Sci USA, 100 (1): 307-12. [PMID:12518067]
27. Hirtz JJ, Braun N, Griesemer D, Hannes C, Janz K, Löhrke S, Müller B, Friauf E. (2012) Synaptic refinement of an inhibitory topographic map in the auditory brainstem requires functional Cav1.3 calcium channels. J Neurosci, 32 (42): 14602-16. [PMID:23077046]
28. Hofer NT, Tuluc P, Ortner NJ, Nikonishyna YV, Fernándes-Quintero ML, Liedl KR, Flucher BE, Cox H, Striessnig J. (2020) Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder. Mol Autism, 11 (1): 4. [PMID:31921405]
29. Huang H, Yu D, Soong TW. (2013) C-terminal alternative splicing of CaV1.3 channels distinctively modulates their dihydropyridine sensitivity. Mol Pharmacol, 84 (4): 643-53. [PMID:23924992]
30. Ihara Y, Yamada Y, Fujii Y, Gonoi T, Yano H, Yasuda K, Inagaki N, Seino Y, Seino S. (1995) Molecular diversity and functional characterization of voltage-dependent calcium channels (CACN4) expressed in pancreatic beta-cells. Mol Endocrinol, 9 (1): 121-30. [PMID:7760845]
31. Jenkins MA, Christel CJ, Jiao Y, Abiria S, Kim KY, Usachev YM, Obermair GJ, Colbran RJ, Lee A. (2010) Ca2+-dependent facilitation of Cav1.3 Ca2+ channels by densin and Ca2+/calmodulin-dependent protein kinase II. J Neurosci, 30 (15): 5125-35. [PMID:20392935]
32. Kersten FF, van Wijk E, van Reeuwijk J, van der Zwaag B, Märker T, Peters TA, Katsanis N, Wolfrum U, Keunen JE, Roepman R et al.. (2010) Association of whirlin with Cav1.3 (alpha1D) channels in photoreceptors, defining a novel member of the usher protein network. Invest Ophthalmol Vis Sci, 51 (5): 2338-46. [PMID:19959638]
33. Kim S, Yun HM, Baik JH, Chung KC, Nah SY, Rhim H. (2007) Functional interaction of neuronal Cav1.3 L-type calcium channel with ryanodine receptor type 2 in the rat hippocampus. J Biol Chem, 282 (45): 32877-89. [PMID:17823125]
34. Klugbauer N, Marais E, Hofmann F. (2003) Calcium channel alpha2delta subunits: differential expression, function, and drug binding. J Bioenerg Biomembr, 35 (6): 639-47. [PMID:15000524]
35. Koschak A, Reimer D, Huber I, Grabner M, Glossmann H, Engel J, Striessnig J. (2001) alpha 1D (Cav1.3) subunits can form l-type Ca2+ channels activating at negative voltages. J Biol Chem, 276 (25): 22100-6. [PMID:11285265]
36. Koschak A, Reimer D, Walter D, Hoda JC, Heinzle T, Grabner M, Striessnig J. (2003) Cav1.4alpha1 subunits can form slowly inactivating dihydropyridine-sensitive L-type Ca2+ channels lacking Ca2+-dependent inactivation. J Neurosci, 23 (14): 6041-9. [PMID:12853422]
37. Lieb A, Scharinger A, Sartori S, Sinnegger-Brauns MJ, Striessnig J. (2012) Structural determinants of CaV1.3 L-type calcium channel gating. Channels (Austin), 6 (3): 197-205. [PMID:22760075]
38. Limpitikul WB, Dick IE, Ben-Johny M, Yue DT. (2016) An autism-associated mutation in CaV1.3 channels has opposing effects on voltage- and Ca(2+)-dependent regulation. Sci Rep, 6: 27235. [PMID:27255217]
39. Mangoni ME, Couette B, Bourinet E, Platzer J, Reimer D, Striessnig J, Nargeot J. (2003) Functional role of L-type Cav1.3 Ca2+ channels in cardiac pacemaker activity. Proc Natl Acad Sci USA, 100 (9): 5543-8. [PMID:12700358]
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target has curated data in GtoImmuPdb
