Key result
The Kir3.2 G156S mutation induces loss of K+ selectivity by forming a novel Li+ permeable and blocker-resistant ion permeation pathway in addition to the central selectivity filter pathway.
Why the study?
Disease-associated mutations of GIRK channels are known to induce loss of K+ selectivity, but the underlying structural changes remain unclear.
The study reveals that the loss of K+ selectivity in the inherited Kir3.2 G156S mutant is due to the formation of a novel ion permeation pathway alongside the central pore.
Mechanistic data on GIRK mutant selectivity loss extend channel biophysics; clinical relevance in channelopathies remains open.
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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Chen et al. (2021) studied Inherited mutant of G-protein-gated inwardly rectifying K+ channel. Kir3.2 G156S mutation vs. Other GIRK mutants was evaluated on Ion selectivity and permeation pathway. The Kir3.2 G156S mutation induces loss of K+ selectivity by forming a novel Li+ permeable and blocker-resistant ion permeation pathway in addition to the central selectivity filter pathway.
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