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The IKs channel is important for the termination of cardiac action potentials.IKs channels are formed by the voltage dependent K+ cannel subunit KCNQ1 coassembling with the auxiliary subunit KCNE1.Mutations of both the KCNQ1 and KCNE1 subunits account for the majority of the cases of congenital Long QT (LQT) syndrome that can lead to fainting and sudden death due to cardiac arrhythmias.However, for many of these LQT-associated mutations the molecular mechanisms of disease pathogenesis are still unknown.This situation is partly due to a lack of understanding of the structure-function relationship of the IK s channel that is fundamental to channel function.My lab has been studying the molecular mechanism of voltage dependent activation and the modulation by interactions between KCNQ1 and KCNE1 subunits.During IKs channel gating,electrostatic interactions between gating charges in the S4 transmembrane segment and counter charges in other structural domains contribute energetically to voltage dependent activation.These interactions are regulated by KCNE1.We found that both KCNQ1 and KCNE1 interact with a membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2), which is required for IKs channel function.Many LQT-associated mutations alter the residues that are key to the above-mentioned interactions during voltage dependent gating, KCNE1 and PIP2 modulation.By altering gating of some of the LQT-associated mutant IKs channels using experimental interventions we are able to rescue IKs channel wild-type phenotype.