TABLE 3

CaV1.2 channels

Channel name CaV1.2
Description Voltage-gated calcium channel α1 subunit
Other names α1C, cardiac or smooth muscle L-type Ca2+ channel, cardiac or smooth muscle dihydropyridine receptor
Molecular information Human: 2169aa, L29529 (cardiac; PMID: 8392192), 2138aa, Z34815 (fibroblast; PMID: 1316612); 2138aa, AF465484 (jejunum; PMID: 12176756); chr. 12p13.3, CACNA1C, LocusID: 775
Rat: 2169aa, M59786 (aortic smooth muscle; PMID: 2170396); 2140/2143aa, M67516/M67515 (brain; PMID: 1648941); chr. 4q42, Cacna1c, LocusID: 24239
Mouse: 2139aa, L01776 (brain; PMID: 1385406); chr. 6, Cacna1c, LocusID: 12288 (see `Comments')
Associated subunits α2δ, β, γ1,2
Functional assays Patch-clamp (whole-cell, single-channel), calcium imaging, cardiac or smooth muscle contraction hormone secretion
Current ICa,L
Conductance Ba2+ (25pS) > Sr2+ = Ca2+ (9pS)3
Ion selectivity Ca2+ > Sr2+ > Ba2+ ≫ Mg2+ from permeability ratios
Activation Va = —17 mV (in 2 mM Ca2+; HEK cells)4; —4 mV (in 15 mM Ba2+; HEK cells) to —18.8 mV (in 5 mM Ba2+; HEK cells and Xenopus oocytes)5,6,7; τa = 1 ms at +10 mV5
Inactivation Vh = —50 to —60 mV (in 2 mM Ca2+; HEK cells),4 —18 to —42 mV (in 5—15 mM Ba2+; HEK cells)5,7,8,9; τfast = 150 ms, τslow = 1100 ms; 61% inactivated after 250 ms in HEK cells8 (at Vmax in 15 mM Ba2+)4; ∼70% inactivation after 1 s (at Vmax in 2 mM Ca2+)4; inactivation is accelerated with Ca2+ as charge carrier (calcium-dependent inactivation: 86% inactivated after 250 ms8,10)
Activators BayK8644, dihydropyridine agonists, FPL6417610,11
Gating modifiers Dihydropyridine antagonists (e.g., isradipine, IC50 = 7 nM at —60 mV; nimodipine, IC50 = 139 nM at —80 mV)6,9
Blockers Nonselective: Cd2+12; selective for CaV1.x: devapamil (IC50 = 50 nM in 10 mM Ba2+ at —60 mV) and other phenylalkylamines; diltiazem (IC50 = 33 μM in 10 mM Ba2+ at —60 mV and 0.05Hz)12
Radioligands (+)-[3H]isradipine (Kd < 0.1 nM) and other dihydropyridines; (—)-[3H]devapamil (Kd = 2.5 nM), (+)-cis-[3H]diltiazem (Kd = 50 nM)11
Channel distribution Cardiac muscle, smooth muscle (including blood vessels, intestine, lung, uterus); endocrine cells (including pancreatic β-cells, pituitary); neurones13; subcellular localization: concentrated on granule-containing side of pancreatic β-cells14; neurons (preferentially somatodendritic)15
Physiological functions Excitation-contraction coupling in cardiac or smooth muscle, action potential propagation in sinoatrial and atrioventricular node, synaptic plasticity, hormone (e.g., insulin) secretion10,13,16,17
Mutations and pathophysiology Required for normal embryonic development (mouse, zebrafish)18,19; de novo G406R mutation in alternative exon 8A in 1 allele causes Timothy syndrome20
Pharmacological significance Mediates cardiovascular effects of clinically used Ca2+ antagonists17; high concentrations of dihydropyridines exert antidepressant effects through Cav1.2 inhibition17
Comments Tissue-specific splice variants exist—in addition to cardiac channels, smooth muscle and brain channels have been cloned7,21,22; the gene for Cav1.2 was first isolated and characterized in rabbit heart (2171aa, P15381, X15539)

  • aa, amino acids; chr., chromosome; HEK, human embryonic kidney.

  • ↵1. Cooper CL, Vandaele S, Barhanin J, Fosset M, Lazdunski M, and Hosey MM (1987) Purification and characterization of the dihydropyridine-sensitive voltage-dependent calcium channel from cardiac tissue. J Biol Chem 262:509-512

  • ↵2. Reimer D, Huber IG, Garcia ML, Haase H, and Striessnig J (2000) Beta subunit heterogeneity of L-type calcium channels in smooth muscle tissues. FEBS Lett 467:65-69

  • ↵3. Tsien RW, Hess P, McCleskey EW, and Rosenberg RL (1987) Calcium channels: mechanisms of selectivity, permeation, and block. Annu Rev Biophys Biophys Chem 16:265-290

  • ↵4. Hu H and Marban E (1998) Isoform-specific inhibition of L-type calcium channels by dihydropyridines is independent of isoform-specific gating properties. Mol Pharmacol 53:902-907

  • ↵5. 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

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

  • ↵7. Tang ZZ, Liang MC, Lu S, Yu D, Yu CY, Yue DT, and Soong TW (2004) Transcript scanning reveals novel and extensive splice variations in human l-type voltage-gated calcium channel, Cav1.2 α1 subunit. J Biol Chem 279:44335-44343

  • ↵8. Koschak A, Reimer D, Walter D, Hoda JC, Heinzle T, Grabner M, and Striessnig J (2003) Cav1.4 α1 subunits can form slowly inactivating dihydropyridine-sensitive L-type Ca2+ channels lacking Ca2+-dependent inactivation. J Neurosci 23:6041-6049

  • ↵9. Peterson BZ, Johnson BD, Hockerman GH, Acheson M, Scheuer T, and Catterall WA (1997) Analysis of the dihydropyridine receptor site of L-type calcium channels by alanine-scanning mutagenesis. J Biol Chem 272:18752-18758

  • ↵10. Striessnig J (1999) Pharmacology, structure and function of cardiac L-type calcium channels. Cell Physiol Biochem 9:242-269

  • ↵11. Glossmann H and Striessnig J (1990) Molecular properties of calcium channels. Rev Physiol Biochem Pharmacol 114:1-105

  • ↵12. Hockerman GH, Johnson BD, Abbott MR, Scheuer T, and Catterall WA (1997) Molecular determinants of high affinity phenylalkylamine block of L-type calcium channels in transmembrane segment IIIS6 and the pore region of the alpha1 subunit. J Biol Chem 272:18759-18765

  • ↵13. Catterall WA (2001) Structure and regulation of voltage-gated calcium channels. Annu Rev Cell Dev Biol 16:521-555

  • ↵14. Bokvist K, Eliasson L, Ämmälä C, Renstrom E, and Rorsman P (1995) Co-localization of L-type calcium channels and insulin-containing secretory granules and its significance for the initiation of exocytosis in mouse pancreatic B-cells. EMBO J 14:50-57

  • ↵15. 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 alpha 1 subunits. J Cell Biol 123:949-962

  • ↵16. 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

  • ↵17. 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 β-cell-selective Cav1.2 Ca2+ channel null mice. EMBO J 22:3844-3854

  • ↵18. Seisenberger C, Specht V, Welling A, Platzer J, Pfeifer A, Kuhbandner S, Striessnig J, Klugbauer N, Feil R, and Hofmann F (2000) Functional embryonic cardio-myocytes after disruption of the L-type αC (Cav1.2) calcium channel gene in the mouse. J Biol Chem 275:39193-39199

  • ↵19. Rottbauer W, Baker K, Wo ZG, Mohideen MA, Cantiello HF, and Fishman MC (2001) Growth and function of the embryonic heart depend upon the cardiac-specific L-type calcium channel α1 subunit. Dev Cell 1:265-275

  • ↵20. CACNA1C; OMIM no. 114205

  • ↵21. Snutch TP, Tomlinson WJ, Leonard JP, and Gilbert MM (1991) Distinct calcium channels are generated by alternative splicing and are differentially expressed in the mammalian CNS. Neuron 7:45-57

  • ↵22. Welling A, Ludwig A, Zimmer S, Klugbaue r N, Flockerzi V, Hofmann F (1997) Alternatively spliced IS6 segments of the α1C gene determine the tissue-specific dihydropyridine sensitivity of cardiac and vascular smooth muscle L-type calcium channels. Circ Res 81:526-532