Regulation of the cardiac L-type Ca2+ channel by the actin-binding proteins alpha-actinin and dystrophin

Theactin-binding proteins dystrophin and -actinin are members of afamily of actin-binding proteins that may link the cytoskeleton tomembrane proteins such as ion channels. Previous work demonstrated thatthe activity of Ca²⁺ channels can be regulated by agentsthat disrupt or stabilize the cytoskeleton. In the present study, weemployed immunohistochemical and electrophysiological techniques toinvestigate the potential regulation of cardiac L-type Ca²⁺channel activity by dystrophin and -actinin in cardiac myocytes andin heterologous cells. Both actin-binding proteins were found tocolocalize with the Ca²⁺ channel in mouse cardiac myocytesand to modulate channel function. Inactivation of the Ca²⁺channel in cardiac myocytes from mice lacking dystrophin(mdx mice) was reduced compared with that in wild-typemyocytes, voltage dependence of activation was shifted by 5 mV to morepositive potentials, and stimulation by the -adrenergic pathway andthe dihydropyridine agonist BAY K 8644 was increased. Furthermore, heterologous coexpression of the Ca²⁺ channel with muscle,but not nonmuscle, forms of -actinin was also found to reduceinactivation. As might be predicted from a reduction ofCa²⁺ channel inactivation, a prolonging of the mouseelectrocardiogram QT was observed in mdx mice. These resultssuggest a combined role for dystrophin and -actinin in regulatingthe activity of the cardiac L-type Ca²⁺ channel and apotential mechanism for cardiac dysfunction in Duchenne and Beckermuscular dystrophies.