CALCIUM CHANNELS - STRUCTURE, FUNCTION, AND CLASSIFICATION

Voltage-gated Ca2+ channels have been extensively characterized in terms of their electrophysiological and pharmacological properties [McDonald et al. (1994): Physiol Rev 74:365-507; Spedding and Paoletti (1992): Pharmacol Rev 44:363-376; Tsien and Tsien (1990): Annu Rev Cell Biol 6:715-760]. These studies indicate that there are numerous types of Ca2+ channels, termed L, N, P/Q, R, and T [Zhang et al. (1993): Neuropharmacology 32:1075-1088]. Biochemical and molecular biological studies have established that Ca2+ channels are multi-subunit complexes composed of an ion-conducting subunit, alpha 1 (see Fig. 1), and smaller accessory subunits (alpha(2), beta, and sometimes gamma and a 95 kDa protein). To date (May, 1994), genes for six alpha 1 four beta, one alpha 2, and one gamma have been cloned. Expression studies with cloned alpha 1 have demonstrated that this subunit can determine the voltage and pharmacological sensitivity of the channel. This should allow us to classify the cloned alpha(1)s in terms of their type. Unfortunately life is not that simple. We will review how the accessory subunits are capable of modifying the pharmacological and biophysical characteristics of the channel. Despite these complications, 5 of the 6 alpha(1)s can be classified as follows: (1) three alpha(1)S (alpha(1S), alpha(1C), and alpha(1D)) belong to the L-type (dihydropyridine-sensitive), (2) alpha(1B) is an N-type (omega-conotoxin-GVIA-sensitive), and (3) alpha(1A) is a P (omega-aga-IVA-sensitive, also called Q [see Zhang et al. (1993): Neuropharmacology 32:1075-1088], herein referred to as P/Q). The sixth alpha(1), alpha(1E), does not display any distinctive pharmacology, thus it has been called an R-type (resistant). The molecular biology of Ca2+ channels has its origins in the biochemical characterization of the skeletal muscle dihydropyridine receptor. This receptor/channel complex was purified, sequenced, cloned, and expressed. Cloning of these cDNAs provided the probes to discover the molecular diversity of Ca2+ channels. We will review the cloning, tissue distribution, and functional expression of alpha(1) subunits following a historical path, then review the accessory subunits. (C) 1994 Wiley-Liss, Inc.