Abstract
The Kir4.1 channel is expressed in the brainstem, retina and kidney. Its heteromerization with Kir5.1 leads to K+ currents with distinct properties such as single‐channel conductance, rectification, pH sensitivity and phosphorylation modulations. Here we show that Kir5.1 also enables S‐glutathionylation to the heteromeric channel. The studies were performed in Kir4.1 and Kir4.1‐Kir5.1 channels expressed in HEK‐293 cells. Exposure to the oxidant H2O2 or diamide (DIA) produced concentration‐dependent inhibitions of the whole‐cell Kir4.1‐Kir5.1 currents. In the inside‐out patches, the currents were inhibited by a combination of 100μM DIA and 100μM GSH (76.5±14.7%, n=4) or 5mM GSSG (57.5±6.6%, n=4). The Kir4.1‐Kir5.1 currents were also strongly inhibited by several 2‐pyridinedisulfides (2‐PDS), thiol modification reagents. In contrast, none of the DIA/GSH, GSSG and 2‐PDS exposures had effects on the homomeric Kir4.1 channel. The finding that the heteromeric Kir4.1‐Kir5.1 but not homomeric Kir4.1 channel is subject to the S‐glutathionylation modulation suggests a novel regulation mechanism that may be involved in the dysfunction of the heteromeric Kir4.1‐Kir5.1 channel in oxidative stress.
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