Palmitoylation of the K <sub>ATP</sub> channel Kir6.2 subunit promotes channel opening by regulating PIP <sub>2</sub> sensitivity
Hua-Qian Yang, Wilnelly Martinez‐Ortiz, JongIn Hwang, Xuexin Fan, Timothy Cardozo, William A. Coetzee
Abstract
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.