Regulation of the cardiac L-type Ca channel by the actin-binding proteins -actinin and dystrophin

Sadeghi, Abbas, Andrew D. Doyle, and Barry D. Johnson. Regulation of the cardiac L-type Ca2 channel by the actin-binding proteins -actinin and dystrophin. Am J Physiol Cell Physiol 282: C1502–C1511, 2002. First published February 13, 2002; 10.1152/ajpcell.00435.2001.—The actin-binding proteins dystrophin and -actinin are members of a family of actin-binding proteins that may link the cytoskeleton to membrane proteins such as ion channels. Previous work demonstrated that the activity of Ca2 channels can be regulated by agents that disrupt or stabilize the cytoskeleton. In the present study, we employed immunohistochemical and electrophysiological techniques to investigate the potential regulation of cardiac L-type Ca2 channel activity by dystrophin and -actinin in cardiac myocytes and in heterologous cells. Both actin-binding proteins were found to colocalize with the Ca2 channel in mouse cardiac myocytes and 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-type myocytes, voltage dependence of activation was shifted by 5 mV to more positive potentials, and stimulation by the -adrenergic pathway and the 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 reduce inactivation. As might be predicted from a reduction of Ca2 channel inactivation, a prolonging of the mouse electrocardiogram QT was observed in mdx mice. These results suggest a combined role for dystrophin and -actinin in regulating the activity of the cardiac L-type Ca2 channel and a potential mechanism for cardiac dysfunction in Duchenne and Becker muscular dystrophies.