Deletion of the Distal C Terminus of CaV1.2 Channels Leads to Loss of β-Adrenergic Regulation and Heart Failure in Vivo
Deletion of the Distal C Terminus of CaV1.2 Channels Leads to Loss of β-Adrenergic Regulation and Heart Failure in Vivo
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DOI：
10.1074/jbc.m110.175307
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发表时间：
2011-04-08
影响因子：
4.8
通讯作者：
Catterall, William A.
中科院分区：
文献类型：
--
作者：
Fu, Ying;Westenbroek, Ruth E.;Catterall, William A.
由Ca（V）1.2通道传导的L型钙电流启动心脏和血管平滑肌的兴奋-收缩偶联。在心脏中，C末端（DCT）的远端部分在体内被蛋白水解处理，并作为Ca（V）1.2通道活性的非共价相关自身抑制剂。这种自身抑制复合物，与A-激酶锚定蛋白-15（AKAP 15）结合到DCT，被假设为在战斗或逃跑反应中β-肾上腺素能调节的底物。表达Ca（V）1.2通道且远端C末端缺失（DCT-/-）的小鼠发生心脏肥大并在E15后过早死亡。通过降低外周血管阻力和高血压的药物治疗，心脏肥大和存活率得到改善，这与血管平滑肌中Ca（V）1.2过度活化导致高血压、肥大和过早死亡的假设一致。然而，与预期相反，DCT-/-小鼠心肌细胞中的L型Ca 2+电流由于细胞表面Ca（V）1.2蛋白表达的减少而显著降低，并且激活的电压依赖性和失活的动力学被改变。在DCT-/-心肌细胞中的Ca（V）1.2通道不能响应于由forskolin激活的腺苷酸环化酶，并且AKAP 15的局部表达减少。因此，我们得出结论，在体内正常的血管调节，心肌细胞中的Ca（V）1.2通道的细胞表面表达，和β-肾上腺素能刺激心脏中的L-型钙电流的Ca（V）1.2通道的DCT是必需的。
L-type calcium currents conducted by Ca(V)1.2 channels initiate excitation-contraction coupling in cardiac and vascular smooth muscle. In the heart, the distal portion of the C terminus (DCT) is proteolytically processed in vivo and serves as a noncovalently associated autoinhibitor of Ca(V)1.2 channel activity. This autoinhibitory complex, with A-kinase anchoring protein- 15 (AKAP15) bound to the DCT, is hypothesized to serve as the substrate for beta-adrenergic regulation in the fight-or-flight response. Mice expressing Ca(V)1.2 channels with the distal C terminus deleted (DCT-/-) develop cardiac hypertrophy and die prematurely after E15. Cardiac hypertrophy and survival rate were improved by drug treatments that reduce peripheral vascular resistance and hypertension, consistent with the hypothesis that Ca(V)1.2 hyperactivity in vascular smooth muscle causes hypertension, hypertrophy, and premature death. However, in contrast to expectation, L-type Ca2+ currents in cardiac myocytes from DCT-/- mice were dramatically reduced due to decreased cell-surface expression of Ca(V)1.2 protein, and the voltage dependence of activation and the kinetics of inactivation were altered. Ca(V)1.2 channels in DCT-/- myocytes fail to respond to activation of adenylyl cyclase by forskolin, and the localized expression of AKAP15 is reduced. Therefore, we conclude that the DCT of Ca(V)1.2 channels is required in vivo for normal vascular regulation, cell-surface expression of Ca(V)1.2 channels in cardiac myocytes, and beta-adrenergic stimulation of L-type Ca2+ currents in the heart.