A novel ion conducting route besides the central pore in an inherited mutant of G-protein-gated inwardly rectifying K+ channel

G蛋白偶联内向整流钾通道 爪蟾 化学 突变体 渗透 选择性 生物物理学 离子通道 生物化学 G蛋白 生物 信号转导 基因 受体 催化作用
作者
I‐Shan Chen,Jodene Eldstrom,David Fedida,Yoshihiro Kubo
标识
DOI:10.1101/2021.08.18.456735
摘要

Abstract G-protein-gated inwardly rectifying K + (GIRK; Kir3.x) channels play important physiological roles in various organs. Some of the disease-associated mutations of GIRK channels are known to induce loss of K + selectivity but their structural changes remain unclear. In this study, we investigated the mechanisms underlying the abnormal ion selectivity of inherited GIRK mutants. By the two-electrode voltage-clamp analysis of GIRK mutants heterologously expressed in Xenopus oocytes, we observed that Kir3.2 G156S permeates Li + better than Rb + , while T154del or L173R of Kir3.2 and T158A of Kir3.4 permeate Rb + better than Li + , suggesting a unique conformational change in the G156S mutant. Applications of blockers of the selectivity filter (SF) pathway, Ba 2+ or Tertiapin-Q (TPN-Q), remarkably increased the Li + -selectivity of Kir3.2 G156S but did not alter those of the other mutants. In single-channel recordings of Kir3.2 G156S expressed in mouse fibroblasts, two types of events were observed, one attributable to a TPN-Q sensitive K + current and the second a TPN-Q resistant Li + current. The results show that a novel Li + permeable and blocker-resistant pathway exists in G156S in addition to the SF pathway. Mutations in the pore helix (PH), S148F and T151A, also induced high Li + permeation. Our results demonstrate that the mechanism underlying the loss of K + selectivity of Kir3.2 G156S involves formation of a novel ion permeation pathway besides the SF pathway, which allows permeation of various species of cations.
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