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Molecular Basis of Multiple Open States in Smooth Muscle Calcium Channels and Related Intracellular Signalling

平滑肌钙通道多重开放状态的分子基础及相关细胞内信号传导

基本信息

批准号：
13670041
负责人：
NAKAYAMA Shinsuke
金额：
$ 1.86万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

It is known that some smooth muscles possess both low- (LVA) and high voltage-activated (HVA) Ca^<2+> channel currents, and that the HVA current component is predominant in all smooth muscles. Previously, we have suggested that the conversion of the Ca^<2+> channel conformation from normal open (O1) to a second open state (O2) during large depoalrization is distinct from the long channel opening induced by Ca^<2+> channel agonists, and that these two mechanisms operate separately. As a result, a combination of DHP Ca^<2+> channel agonists and depolarization produces at least four open states in native smooth muscle Ca^<2+> channels.During the tenure of the present research project entitled 'Molecular Basis of Multiple Open States in Smooth Muscle Calcium Channels and Related Intracellular Signalling', we have first examined whether the multiple open state model can systematically account for the characteristic features of 'U-shaped inactivation' and 'slow deactivation' in CHO cells exp … More ressing only smooth muscle _1 subunit of L-type Ca^<2+> channel (Ca,1.2b), using patch clamp techniques. The experiments have revealed that smooth muscle _1 subunit alone can reproduce 'U-shaped inactivation' and 'slow deactivation' properties, and also interaction of highly positive conditioning steps and Ca^<2+> agonists. The results imply that intramolecular structural changes and/or interactions in _1 subunit protein play the central roles. Furthermore, we have reconstructed the slow deactivation and U-shaped inactivation properties seen in cloned smooth muscle Ca^<2+> channels using computer calculation with multiple open state models. Taken Together, it is concluded that that the conformation of _1 subunit of L-type Ca2+ channel can be converted from O1 to O2 state in a voltage-dependent manner. This conversion is not predicted from the gating model described by Hodgkin & Huxley. We would like to propose that some modification in this basic model is presumably necessary to describe gating kinetics under more general conditions. Less

已知某些平滑肌同时具有低电压激活（LVA）和高电压激活（HVA）Ca^2+通道电流，并且HVA电流成分在所有平滑肌中占主导地位。以前，我们已经提出，在大的去极化过程中，Ca^2+通道构象从正常开放状态（O 1）转变为第二开放状态（O2），这与Ca^2+通道激动剂诱导的长通道开放不同，并且这两种机制分别起作用。因此，DHP Ca^<2+>通道激动剂和去极化的组合在天然平滑肌Ca^<2+>通道中产生至少四种开放状态。在本研究项目题为“平滑肌钙通道和相关细胞内信号的多个开放状态的分子基础”的任期内，我们首先检验了多重开放状态模型是否能系统地解释CHO细胞中的“U形失活”和“缓慢失活”的特征， ...更多信息采用膜片钳技术，仅对平滑肌细胞L型Ca^2+通道（Ca，1.2b）的1亚单位进行记录。实验结果表明，平滑肌_1亚基单独存在时，可再现“U形失活”和“缓慢失活”特性，也可再现高度正性条件化步骤和Ca^<2+>激动剂的相互作用。结果表明，_1亚基蛋白的分子内结构变化和/或相互作用起主要作用。此外，我们利用计算机计算的多个开放态模型，重建了在克隆的平滑肌Ca^2+通道中观察到的缓慢失活和U形失活特性。综上所述，L型Ca 2+通道_1亚基的构象可以以电压依赖性的方式从O 1态转变为O2态。这种转换不是由Hodgkin & Huxley描述的门控模型预测的。我们想提出，在这个基本模型的一些修改大概是必要的，以描述门控动力学在更一般的条件下。少