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

Regulation of the cardiac L-type Ca2+ channel by the actin-binding proteins α-actinin and dystrophin Abstract 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. muscular dystrophy intracellular regulation Footnotes This work was supported by an American Heart Association Scientist Development Grant (B. D. Johnson) and by start-up funds from the University of Connecticut Research Foundation. Address for reprint requests and other correspondence: B. D. Johnson, Dept. of Pharmacology and Therapeutics, Univ. of British Columbia, 3650 Wesbrook Mall, Vancouver, Canada BC V6S 2L2 (E-mail: barrydjohnson@telus.net ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. First published February 13, 2002;10.1152/ajpcell.00435.2001 Copyright © 2002 the American Physiological Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP - Cell Physiology The American Physiological Society

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

Sadeghi, Abbas; Doyle, Andrew D.; Johnson, Barry D.
AJP - Cell Physiology , Volume 282 (6): C1502 – Jun 1, 2002
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References (32)

Publisher
The American Physiological Society
Copyright
Copyright © 2010 the American Physiological Society
ISSN
0363-6143
eISSN
1522-1563
DOI
10.1152/ajpcell.00435.2001
pmid
11997265
Publisher site
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Abstract

Abstract 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. muscular dystrophy intracellular regulation Footnotes This work was supported by an American Heart Association Scientist Development Grant (B. D. Johnson) and by start-up funds from the University of Connecticut Research Foundation. Address for reprint requests and other correspondence: B. D. Johnson, Dept. of Pharmacology and Therapeutics, Univ. of British Columbia, 3650 Wesbrook Mall, Vancouver, Canada BC V6S 2L2 (E-mail: barrydjohnson@telus.net ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. First published February 13, 2002;10.1152/ajpcell.00435.2001 Copyright © 2002 the American Physiological Society

Journal

AJP - Cell Physiology – The American Physiological Society

Published: Jun 1, 2002

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