title: Regulation of the cardiac L-type Ca2+ channel by the actin-binding proteins alpha-actinin and dystrophin.
abstract: The actin-binding proteins dystrophin and alpha-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 alpha-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 beta-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 alpha-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 alpha-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.
authors: Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut 06269.
authors: Abbas
authors: A
authors: Sadeghi
authors: Andrew D
authors: AD
authors: Doyle
authors: Barry D
authors: BD
authors: Johnson
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000185:Actinin / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016189:Dystrophin / Q000378:metabolism*; D004562:Electrocardiography; D005455:Fluorescent Antibody Technique; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D009137:Muscular Dystrophy, Animal / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D020033:Protein Isoforms / Q000378:metabolism; D011817:Rabbits; D051381:Rats
chemical_list: D000318:Adrenergic beta-Agonists; D002120:Calcium Channel Agonists; D020746:Calcium Channels, L-Type; D016189:Dystrophin; D020033:Protein Isoforms; D000185:Actinin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester