Differential effects of amino-terminal distal and proximal domains in the regulation of human erg K+ channel gating
Differential effects of amino-terminal distal and proximal domains in the regulation of human erg K+ channel gating
复制标题
DOI：
10.1016/s0006-3495(00)76286-2
复制
发表时间：
2000-07-01
影响因子：
3.4
通讯作者：
de la Peña, P
中科院分区：
文献类型：
--
作者：
Viloria, CG;Barros, F;de la Peña, P
氨基端结构域参与人类ether-a-go-go（eag）相关基因（HERG）K+的表达。使用在非洲爪蟾卵母细胞中表达的缺失的通道变体研究通道门控。选择性缺失位于保守的初始氨基末端（eag或PAS结构域）和第一跨膜螺旋之间的HERG特异性序列（HERG Delta 138-373）加速通道激活并将其电压依赖性转变为超极化值，然而，从完全激活状态和通道失活的失活时间常数在缺失后几乎保持不变。缺失效应同样表现在缺乏失活的通道变体中。仅缺少约一半的HERG特异性结构域（Delta 223-373）或19个残基的短片段（Delta 355-373）的构建体的特征表明，该结构域的作用不仅与其长度相关，而且与通道核心附近存在的特异性序列相关。缺失诱导的效应被eag结构域的额外消除部分逆转。因此，HERG特异性和eag结构域的特定组合决定了两个重要的HERG特征：神经元尖峰频率适应和心脏动作电位平台维持所必需的缓慢激活，以及有助于HERG内向整流的缓慢失活。
The participation of amino-terminal domains in human ether-a-go-go (eag)-related gene (HERG) K+. channel gating was studied using deleted channel variants expressed in Xenopus oocytes. Selective deletion of the HERG-specific sequence (HERG Delta 138-373) located between the conserved initial amino terminus (the eag or PAS domain) and the first transmembrane helix accelerates channel activation and shifts its voltage dependence to hyperpolarized values, However, deactivation time constants from fully activated states and channel inactivation remain almost unaltered after the deletion. The deletion effects are equally manifested in channel variants lacking inactivation. The characteristics of constructs lacking only about half of the HERG-specific domain (Delta 223-373) or a short stretch of 19 residues (Delta 355-373) suggest that the role of this domain is not related exclusively to its length, but also to the presence of specific sequences near the channel core. Deletion-induced effects are partially reversed by the additional elimination of the eag domain. Thus the particular combination of HERG-specific and eag domains determines two important HERG features: the slow activation essential for neuronal spike-frequency adaptation and maintenance of the cardiac action potential plateau, and the slow deactivation contributing to HERG inward rectification.