Sadeghi Abbas, Doyle Andrew D, Johnson Barry D
Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut 06269.
Am J Physiol Cell Physiol. 2002 Jun;282(6):C1502-11. doi: 10.1152/ajpcell.00435.2001.
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.
肌动蛋白结合蛋白肌营养不良蛋白和α-辅肌动蛋白是肌动蛋白结合蛋白家族的成员，它们可能将细胞骨架与离子通道等膜蛋白连接起来。先前的研究表明，钙通道的活性可受破坏或稳定细胞骨架的药物调节。在本研究中，我们采用免疫组织化学和电生理技术，研究肌营养不良蛋白和α-辅肌动蛋白对心肌细胞和异源细胞中心脏L型钙通道活性的潜在调节作用。发现这两种肌动蛋白结合蛋白在小鼠心肌细胞中均与钙通道共定位，并调节通道功能。与野生型心肌细胞相比，缺乏肌营养不良蛋白的小鼠（mdx小鼠）心肌细胞中钙通道的失活减少，激活的电压依赖性向更正电位偏移5 mV，β-肾上腺素能途径和二氢吡啶激动剂BAY K 8644的刺激增强。此外，还发现钙通道与肌肉型而非非肌肉型α-辅肌动蛋白的异源共表达也可减少失活。正如从钙通道失活减少所预测的那样，在mdx小鼠中观察到心电图QT间期延长。这些结果表明肌营养不良蛋白和α-辅肌动蛋白在调节心脏L型钙通道活性中具有联合作用，并且是杜兴氏和贝克氏肌营养不良症中心脏功能障碍的潜在机制。
