Tyrosine phosphorylation of Kir6.2 subunit negatively regulates cardiac K(ATP) 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.