CaV1.3 channels

Channel name CaV1.3
Description Voltage-gated calcium channel α1 subunit
Other names α1D, “neuroendocrine” L-type Ca2+ channel
Molecular information Human: 2161aa, M76558 (brain; PMID: 1309651); 2181aa, M83566 (pancreatic β-cells; PMID: 1309948); chr. 3p14.3, CACNA1D, LocusID: 776
Rat: 1646aa, M57682 (brain; PMID: 1648940); 2203aa, D38101 (pancreatic β-cells; PMID: 7760845); chr. 16p16, Cacna1d, LocusID: 29716
Mouse: 2144aa, AJ437291 (embryonic heart; PMID: 12900400); chr. 14, Cacna1d, LocusID: 12289 (see “Comments”)
Associated subunits Most likely at least α2, β, and δ subunits
Functional assays Patch-clamp (whole-cell, single-channel), calcium imaging
Current ICa,L
Conductance Not established
Ion selectivity Not established
Activation Va = —15 to —20 mV (mouse cochlear hair cells; 10 mM Ba2+)1,2; —18 mV (in 15 mM Ba2+; HEK cells) to —37 mV (5 mM Ba2+; 2 mM Ca2+ HEK cells or Xenopus oocytes)3,4; τa < 1 ms at +10 mV3
Inactivation Vh = —36 to —43 mV3,5; τfast = 190 ms, τslow = 1700 ms (at Vmax in HEK cells)3; calcium-induced inactivation is observed after expression in HEK cells3 and in cochlear outer hair cells but not in inner hair cells2
Activators BayK86441,2,3,4,5
Gating modifiers Dihydropyridine antagonists (e.g., isradipine, IC50 = 30 nM at —50 mV and 300 nM at —90 mV; nimodipine, IC50 = 3 μM at —80 mV)3,4
Blockers Nonselective: Cd2+5
Radioligands (+)-[3H]isradipine (Kd < 0.5 nM)3; in radioreceptor assays, HEK cell-expressed Cav1.2 and Cav1.3 channels bind (+)-[3H]isradipine with indistinguishable KD3; in functional experiments, however, Cav1.2 channels show higher DHP sensitivity—this discrepancy is explained by the slower inactivation of Cav1.3 decreasing the availability of inactivated channels for state-dependent DHP block
Channel distribution Sensory cells (photoreceptors, cochlear hair cells1,2), endocrine cells (including pancreatic β-cells, pituitary, adrenal chromaffin cells, pinealocytes),7,8,9 low density in heart (atrial muscle, sinoatrial and atrioventricular node)1,7,10 and vascular smooth muscle7; neurones6; subcellular localization: on neurones preferentially located on proximal dendrites and cell bodies6
Physiological functions Neurotransmitter release in sensory cells, control of cardiac rhythm and atrioventricular node conductance at rest,1,10,12 mood behavior,12 hormone secretion
Mutations and pathophysiology Deafness, sinoatrial and atrioventricular node dysfunction,1,10,12 no convincing evidence for contribution to pancreatic β-cell L-type currents and insulin secretion in mouse models1,12,13
Pharmacological significance Hypothetical drug targets for modulators of heart rate,1 antidepressant drugs10 and drugs for hearing disorders1
Comments Tissue-specific and developmental (exon 1b) splice variants exist—in addition to brain, pancreatic β-cell and cochlear variants have been cloned; it is likely that Cav1.3 channels form most of the so-called `low-voltage-activated' L-type currents found in the brain and sinoatrial node, although some splice variants of Cav1.2 can also activate at more negative potentials
  • aa, amino acids; chr., chromosome; HEK, human embryonic kidney; DHP, dihydropyridine.

  • 1. Platzer J, Engel J, Schrott-Fischer A, Stephan K, Bova S, Chen H, Zheng H, and Striessnig J (2000) Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type calcium channels. Cell 102:89-97

  • 2. Michna M, Knirsch M, Hoda JC, Muenkner S, Langer P, Platzer J, Striessnig J, and Engel J (2003) Cav1.3 (α1D) Ca2+ currents in neonatal outer hair cells of mice. J Physiol 553:747-758

  • 3. Koschak A, Reimer D, Huber I, Grabner M, Glossmann H, Engel J, and Striessnig J (2001) α1D (Cav1.3) subunits can form L-type calcium channels activating at negative voltages. J Biol Chem 276:22100-22106

  • 4. Xu W and Lipscombe D (2001) Neuronal Cav1.3α1 L-type channels activate at relatively hyperpolarized membrane potentials and are incompletely inhibited by dihydropyridines. J Neurosci 21:5944-5951

  • 5. Scholze A, Plant TD, Dolphin AC, and Nürnberg B (2001) Functional expression and characterization of a voltage-gated Cav1.3 (α1D) calcium channel subunit from an insulin-secreting cell line. Mol Endocrinol 15:1211-1221

  • 6. Hell JW, Westenbroek RE, Warner C, Ahlijanian MK, Prystay W, Gilbert MM, Snutch TP, and Catterall WA (1993) Identification and differential subcellular localization of the neuronal class C and class D L-type calcium channel α1 subunits. J Cell Biol 123:949-962

  • 7. Takimoto K, Li D, Nerbonne JM, and Levitan ES (1997) Distribution, splicing and glucocorticoid-induced expression of cardiac α1C and α1D voltage-gated calcium channel mRNAs. J Mol Cell Cardiol 29:3035-3042

  • 8. Garcia-Palomero E, Renart J, Andres-Mateos E, Solis-Garrido LM, Matute C, Herrero CJ, Garcia AG, and Montiel C (2001) Differential expression of calcium channel subtypes in the bovine adrenal medulla. Neuroendocrinology 74:251-261

  • 9. Chik CL, Liu QY, Li B, Klein DC, Zylka M, Kim DS, Chin H, Karpinski E, and Ho AK (1997) Alpha 1D L-type Ca2+-channel currents: inhibition by a beta-adrenergic agonist and pituitary adenylate cyclase-activating polypeptide (PACAP) in rat pinealocytes. J Neurochem 68:1078-1087

  • 10. Mangoni ME, Couette B, Bourinet E, Platzer J, Reimer D, Striessnig J, and Nargeot J (2003) Functional role of L-type Cav1.3 Ca2+ channels in cardiac pacemaker activity. Proc Natl Acad Sci USA 100:5543-5548

  • 11. Namkung Y, Skrypnyk N, Jeong MJ, Lee T, Lee MS, Kim HL, Chin H, Suh PG, Kim SS, and Shin HS (2001) Requirement for the L-type calcium channel α1D subunit in postnatal pancreatic beta cell generation. J Clin Investig 108:1015-1022

  • 12. Sinnegger-Brauns MJ, Hetzenauer A, Huber IG, Renstrom E, Wietzorrek G, Berjukov S, Cavalli M, Walter D, Koschak A, Waldschutz R, et al. (2004) Isoform-specific regulation of mood behavior and pancreatic β-cell and cardiovascular function by L-type Ca2+ channels. J Clin Investig 113:1430-1439

  • 13. Schulla V, Renstrom E, Feil R, Feil S, Franklin I, Gjinovci A, Jing XJ, Laux D, Lundquist I, Magnuson MA, et al. (2003) Impaired insulin secretion and glucose tolerance in beta cell-selective Cav1.2 Ca2+ channel null mice. EMBO J 22:3844-3854