Peterson B Z, DeMaria C D, Adelman J P, Yue D T
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Neuron. 1999 Mar;22(3):549-58. doi: 10.1016/s0896-6273(00)80709-6.
Elevated intracellular Ca2+ triggers inactivation of L-type calcium channels, providing negative Ca2+ feedback in many cells. Ca2+ binding to the main alpha1c channel subunit has been widely proposed to initiate such Ca2+ -dependent inactivation. Here, we find that overexpression of mutant, Ca2+ -insensitive calmodulin (CaM) ablates Ca2+ -dependent inactivation in a "dominant-negative" manner. This result demonstrates that CaM is the actual Ca2+ sensor for inactivation and suggests that CaM is constitutively tethered to the channel complex. Inactivation is likely to occur via Ca2+ -dependent interaction of tethered CaM with an IQ-like motif on the carboxyl tail of alpha1c. CaM also binds to analogous IQ regions of N-, P/Q-, and R-type calcium channels, suggesting that CaM-mediated effects may be widespread in the calcium channel family.
细胞内钙离子浓度升高会触发L型钙通道失活，在许多细胞中提供负性钙离子反馈。钙离子与主要的α1c通道亚基结合被广泛认为是启动这种钙离子依赖性失活的原因。在此，我们发现突变型、对钙离子不敏感的钙调蛋白（CaM）的过表达以“显性负性”方式消除了钙离子依赖性失活。这一结果表明CaM是失活的实际钙离子传感器，并提示CaM持续与通道复合物相连。失活可能通过与α1c羧基末端类似IQ基序的相连CaM的钙离子依赖性相互作用而发生。CaM还与N型、P/Q型和R型钙通道的类似IQ区域结合，提示CaM介导的效应可能在钙通道家族中广泛存在。
