Determinants for calmodulin binding on voltage-dependent Ca2+ channels

Calmodulin, bound to the alpha (1) subunit of the cardiac L-type calcium channel, is required for calcium-dependent inactivation of this channel. Several laboratories have suggested that the site of interaction of calmodulin with the channel is an IQ-Like motif in the carboxyl-terminal region of the cu, subunit. Mutations in this IQ motif are linked to L-type Ca2+ current (I-Ca) facilitation and inactivation. IQ peptides from L, P/Q, N, and R channels all bind Ca2+ calmodulin but not Ca2+-free calmodulin. Another peptide representing a carboxyl-terminal sequence found only in L-type channels (designated the CB domain) binds Ca2+ calmodulin and enhances Ca2+ dependent Ic, facilitation in cardiac myocytes, suggesting the CB domain is functionally important. Calmodulin blocks the binding of an antibody specific for the CB sequence to the skeletal muscle L-type Ca2+ channel, suggesting that this is a calmodulin binding site on the intact protein. The binding of the IQ and CB peptides to calmodulin appears to be competitive, signifying that the two sequences represent either independent or alternative binding sites for calmodulin rather than both sequences contributing to a single binding site.