Regulation of the cardiac L-type Ca 2+ channel by the actin-binding proteins α-actinin and dystrophin

• Published in: American Journal of Physiology: Cell Physiology Vol. 282; no. 6; pp. C1502 - C1511
• Main Authors: Sadeghi, Abbas, Doyle, Andrew D., Johnson, Barry D.
• Format: Journal Article
• Language: English
• Published: 01.06.2002
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00435.2001

The actin-binding proteins dystrophin and α-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 Ca 2+ 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 Ca 2+ channel activity by dystrophin and α-actinin in cardiac myocytes and in heterologous cells. Both actin-binding proteins were found to colocalize with the Ca 2+ channel in mouse cardiac myocytes and to modulate channel function. Inactivation of the Ca 2+ 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 β-adrenergic pathway and the dihydropyridine agonist BAY K 8644 was increased. Furthermore, heterologous coexpression of the Ca 2+ channel with muscle, but not nonmuscle, forms of α-actinin was also found to reduce inactivation. As might be predicted from a reduction of Ca 2+ channel inactivation, a prolonging of the mouse electrocardiogram QT was observed in mdx mice. These results suggest a combined role for dystrophin and α-actinin in regulating the activity of the cardiac L-type Ca 2+ channel and a potential mechanism for cardiac dysfunction in Duchenne and Becker muscular dystrophies.