MOLECULAR DETERMINANTS OF CA2+ CHANNEL FUNCTION AND DRUG-ACTION

Molecular cloning has revealed the existence of six high-voltage activated Ca2+ channel types. Expression studies have shown that basic high-voltage activated channel function, which is typical for the L-(skeletal muscle, cardiac muscle and neuroendocrine tissue), N-, P-, Q- and R-type channels is carried by the corresponding alpha1 subunits. Auxiliary subunits, such as alpha2/delta and beta, modulate the kinetics of activation, inactivation current density and drug binding, thereby creating considerable potential for multiple Ca2+ channel functions. Glutamic acid residues in the pore (P) loops are molecular components that impart high selectivity for Ca2+. Binding or pharmacologically active sites for Ca2+ channel drugs have been localized on various segments of the alpha1 subunit in close proximity to the pore lining. In this article, Gyula Varadi and colleagues review the roles of the different subunits in Ca2+ channel function and suggest that Ca2+ channel drugs act by blocking or, in some cases, activating channel function via binding directly or indirectly to the pore structure of the channel.