CaV1.1 channels

Channel name Cav1.1
Description Voltage-gated calcium channel α1-subunit
Other names α1s, skeletal muscle L-type Ca2+ channel, skeletal muscle dihydropyridine receptor
Molecular information Human: 1873aa, L33798 (PMID: 7713519), chr0.1q32, CACNA1S, LocusID: 779
Rat: 1146aa (partial sequence), L04684 (PMID: 1335956), chr. 13, Cacna1s, LocusID: 116652
Mouse: 1861aa, L06234 (PMID: 1281468), chr. 1, Cacna1s, LocusID: 12292 (see `Comments')
Associated subunits α2δ, β, γ1,2
Functional assays Patch-clamp (whole-cell, single-channel), calcium imaging, gating charge movement, skeletal muscle contraction
Current ICa,L
Conductance 13—17pS (in 90—110 mM Ba2+)3,4
Ion selectivity Ca2+ > Sr2+ > Mg2+ > Ba2+5
Activation Va = 8—14 mV, τa > 50 ms at +10 mV (10 mM Ca2+)4,6
Inactivation Vh = —8 mV, 40% current inactivation after 5 s (—5 mV)4
Activators BayK8644, dihydropyridine agonists, FPL641762,8,9
Gating modifiers Dihydropyridine antagonists (e.g., (+)- isradipine; IC50 = 13 nM at —90 mV and 0.15 nM at —65 mV)9
Blockers Nonselective: cadmium (IC50 < 0.5 mM)9; selective for Cav1.x: verapamil, devapamil (IC50 < 1 μM) and other phenylalkylamines, (+)-cis-diltiazem (IC50 < 80 μM)9
Radioligands (+)-[3H]isradipine (Kd = 0.2—0.7 nM) and other dihydropyridines; (—)-[3H]devapamil (Kd = 2.5 nM), (+)-cis-[3H]diltiazem (Kd = 50 nM)2
Channel distribution Skeletal muscle transverse tubules (tetramers)10
Physiological functions Excitation-contraction coupling and Ca2+ homeostasis in skeletal muscle11
Mutations and pathophysiology Point mutations cause hypokalemic periodic paralysis and malignant hyperthermia susceptibility in humans and muscular dysgenesis in mice (mdg / mdg)12,13
Pharmacological significance Not established
Comments The gene for Cav1.1 was first isolated and characterized in rabbit (1873aa, M23919, X05921); several groups reported three-dimensional structures of the purified skeletal muscle calcium channel complex determined using electron cryomicroscopy and single-particle averaging14
  • aa, amino acids; chr., chromosome; Bay K8644, methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5-carbo xylate; FPL64176, methyl 2,5 dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylate.

  • 1. Takahashi M, Seagar MJ, Jones JF, Reber BF, and Catterall WA (1987) Subunit structure of dihydropyridine-sensitive calcium channels from skeletal muscle. Proc Natl Acad Sci USA 84:5478-5482

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

  • 3. Dirksen RT, Nakai J, Gonzales A, Imoto K, and Beam KG (1997) The S5-S6 linker of repeat I is a critical determinant of L-type Ca2+ channel conductance. Biophys J 73:1402-1409

  • 4. Freise D, Held B, Wissenbach U, Pfeifer A, Trost C, Himmerkus N, Schweig U, Freichel M, Biel M, Hoffmann F, et al. (2000) Absence of the γ subunit of the skeletal muscle dihydropyridine receptor increases L-type calcium currents and alters channel inactivation properties. J Biol Chem 275:14476-14481

  • 5. Pizarro G, Fitts R, Uribe I, and Rios E (1989) The voltage-sensor of excitation-contraction coupling in skeletal muscle: ion dependence and selectivity. J Gen Physiol 94:405-428

  • 6. Dirksen RT and Beam KG (1995) Single calcium channel behavior in native skeletal muscle. J Gen Physiol 105:227-247

  • 7. Rovnyak GC, Kimball SD, Beyer B, Cucinotta G, DiMarco JD, Gougoutas J, Hedberg A, Malley M, McCarthy JP, Zhang R, et al. (1995) Calcium entry blockers and activators: conformational and structural determinants of dihydropyrimidine calcium channel modulators. J Med Chem 38:119-129

  • 8. Striessnig J (1999) Pharmacology, structure and function of cardiac L-type Ca2+ channels. Cell Physiol Biochem 9:242-269

  • 9. Glossmann H and Striessnig J (1988) Ca2+ channels. Vitam Horm 44:155-328

  • 10. Flucher BE and Franzini-Armstrong C (1996) Formation of junctions involved in excitation-contraction coupling in skeletal and cardiac muscle. Proc Natl Acad Sci USA 93:8101-8106

  • 11. Rios E, Pizarro G, and Stefani E (1992) Charge movement and the nature of signal transduction in skeletal muscle excitation-contraction coupling. Annu Rev Physiol 54:109-133

  • 12. CACNA1S; Online Mendelian Inheritance in Man (OMIM) no. 114208

  • 13. Striessnig J, Hoda JC, Koschak A, Zaghetto F, Mullner C, Sinnegger-Brauns MJ, Wild C, Watschinger K, Trockenbacher A, and Pelster G (2004) L-type Ca2+ channels in Ca2+ channelopathies. Biochem Biophys Res Commun 322:1341-1346

  • 14. Wang MC, Dolphin A, and Kitmitto A (2004) L-type voltage-gated calcium channels: understanding function through structure. FEBS Lett 564:245-250