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 alpha 1 subunits. Auxiliary subunits, such as alpha 2/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 Ca+. Binding or pharmacologically active sites for Ca2+ channel drugs have been localized on various segments of the alpha 1 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.