Key result
S-palmitoylation of the Kir6.2 subunit increases the K ATP channel open state by increasing sensitivity to PIP2, altering channel regulation by α1-adrenoceptor signaling in cardiomyocytes.
Why the study?
Lipidation is poorly characterized for ion channels, despite posttranslational modifications substantially increasing protein diversity.
S-palmitoylation of the Kir6.2 subunit regulates K ATP channel opening via PIP2 sensitivity, suggesting a novel therapeutic target.
Significance Protein diversity is substantially increased by posttranslational modifications of amino acid residues. Lipidation is poorly characterized for ion channels. We found regulated S-palmitoylation to occur in certain K + channels (Kir3.4, Kir6.1, and Kir6.2). For Kir6.2, lipidation at Cys 166 (or gene variants associated with diabetes) increases the channel open state. Experimental and molecular modeling studies show this due mainly to an increased sensitivity to PIP 2 , which results in altered regulation of K ATP channels by α1-adrenoceptor signaling in cardiomyocytes. Our data demonstrate complexity in the regulation of K ATP channels by long-chain acyl-CoA esters, which can be both acute and direct, but also be mediated through regulated S-palmitoylation. Strategies aimed at regulating the palmitoylation state of K ATP channels may represent new therapeutic opportunities.
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Yang et al. (2020) studied this question. S-palmitoylation of K ATP channels was evaluated on Channel open state and PIP2 sensitivity. S-palmitoylation of the Kir6.2 subunit increases the K ATP channel open state by increasing sensitivity to PIP2, altering channel regulation by α1-adrenoceptor signaling in cardiomyocytes.
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