Molecular basis of inward rectification: Structural features of the blocker defined by extended polyamine analogs
Molecular basis of inward rectification: Structural features of the blocker defined by extended polyamine analogs
复制标题
DOI：
10.1124/mol.105.012377
复制
发表时间：
2005-08-01
影响因子：
3.6
通讯作者：
Nichols, CG
中科院分区：
文献类型：
--
作者：
Loussouarn, G;Marton, LJ;Nichols, CG
多胺通过阻塞通道孔深处来引起 Kir K+ 通道的向内整流。我们研究了强整流突变 K-ATP 通道 (Kir6.2[ L164C, N160D, C166S] + SUR1) 的多胺阻断的结构约束。我们研究了三组多胺类似物：1）在第二和第三胺之间具有环烷基或烯基的构象限制的线性四胺（CGC-11047、CGC-11093、CGC-11099和CGC-11098），2）在第五和第六胺之间具有环烷基或烯基的构象限制的线性十胺(CGC-11150、CGC-11179 和 CGC-11241)，和 3) 环状四胺（CGC-11174、CGC-11197、CGC-11199 和 CGC-11254）。所有线性类似物都会产生与精胺类似的电压依赖性阻断，但稍弱（在 1 μM 时，精胺阻断的 V-1/2 = - 10 +/- 1 mV，Z = 2.9 +/- 0.1，n = 19；多胺类似物的 V-1/2 从 - 7 到 + 10 mV，Z = 2.6 - 3.9）。这些数据表明构象限制的耐受性和阻断过程的电压依赖性的上限。环状化合物不存在电压依赖性阻断；相反，它们会引起电流不可逆转的衰减。 Kir 通道的结构模型表明，细胞质孔顶部的狭窄入口可能将环状类似物排除在内腔之外，从而解释了我们观察到的结构-活性关系。
Polyamines cause inward rectification of Kir K+ channels by blocking deep within the channel pore. We investigated structural constraints of polyamine block of strongly rectifying mutant K-ATP channels (Kir6.2[ L164C, N160D, C166S] + SUR1). We studied three groups of polyamine analogs: 1) conformationally restricted linear tetra-amines with a cycloalkyl or alkene group between the second and third amines (CGC-11047, CGC-11093, CGC-11099, and CGC-11098), 2) conformationally restricted linear deca-amines with a cycloalkyl or alkene group between the fifth and sixth amines (CGC-11150, CGC-11179, and CGC-11241), and 3) cyclic tetra-amines (CGC-11174, CGC-11197, CGC-11199, and CGC-11254). All linear analogs cause a voltage-dependent block similar to that of spermine, but slightly weaker (at 1 mu M, V-1/2 for spermine block = - 10 +/- 1 mV, Z = 2.9 +/- 0.1, n = 19; V-1/2 for polyamine analogs varies from - 7 to + 10 mV, Z = 2.6 - 3.9). These data indicate tolerance for conformational restriction and an upper limit to the voltage dependence of the blocking process. There was no voltage-dependent block by the cyclic compounds; instead, they induce irreversible rundown of the current. Structural models of Kir channels suggest that a narrow entry at the top of the cytoplasmic pore may exclude cyclic analogs from the inner cavity, thereby explaining the structure-activity relationship that we observe.