Tyrosine phosphorylation of Kir6.2 subunit negatively regulates cardiac KATP channel activity

The plasma membrane ATP-sensitive potassium (K_ATP) channel in cardiac myocytes plays a critical role in protecting the heart against ischemic injury. Post-translational modifications regulate K_ATP channel activity and play a role in cardioprotection. However, the role of tyrosine phosphorylation in K_ATP channel regulation remains unclear. In this study, we investigated the cardiac K_ATP channel subtype Kir6.2/SUR2A and demonstrated that a protein tyrosine kinase inhibitor significantly increased the current amplitude through blunting the ATP sensitivity of K_ATP channels without altering the single-channel current or the channel surface expression. Mutation screening identified Y258 in the Kir6.2 subunit as the tyrosine phosphorylation site of the K_ATP channel. In cardiomyocytes, K_ATP channel currents can be reversibly enhanced or weakened by inhibiting the tyrosine kinase epidermal growth factor receptor or the protein tyrosine phosphatase 1B. Furthermore, in a perfused mouse heart model, the inhibitor of epidermal growth factor receptor exhibited a significant cardioprotective effect in a K_ATP channel dependent manner, indicating the pharmacological potential for treatment of ischemic heart disease.