Cardiac I Ks currents, composed of the voltage-gated potassium channel KCNQ1 and its regulatory subunit KCNE1, are essential for controlling cardiac action potential duration and thus regulating heart rhythm. PIP 2 (phosphatidylinositol 4,5-bisphosphate), a membrane phospholipid, is required for the function of both KCNQ1 and I Ks . Our recently solved KCNQ1-KCNE1 structure reveals a PIP 2 molecule (C-PIP 2 ) bound at the voltage sensor domain (VSD)-pore interface, where it facilitates VSD-pore coupling and is essential for I Ks . activation electrophysiological recordings showed that nearly all C-PIP 2 binding site mutants significantly reduced current amplitudes of both KCNQ1 and I Ks , though some exhibited less effect on KCNQ1 than on I Ks , raising the question of whether C-PIP 2 binding differs in the presence versus absence of KCNE1. KCNQ1 adopts bent and straight conformations, opening predominantly in the intermediate open (IO) state with a bent conformation when alone, whereas I Ks opens exclusively in the activated-open (AO) state with a straight conformation. Subsequent molecular docking and electrophysiological analyses reveal that the C-PIP 2 binding site shifts during conformational transitions involving KCNE1. PIP 2 is hydrolyzed by phospholipase C (PLC) upon activation of Gq protein-coupled receptors (GqPCRs). Using the PLC agonist m -3m3FBS to mimic GqPCR activation, we found that I Ks exhibits IC 50 values 10-fold higher than KCNQ1 alone, suggesting that KCNE1 may provide resistance to GqPCR regulation in cardiac cells under physiological conditions. Collectively, our findings establish a novel paradigm for I Ks regulation by PIP 2 .
Zhao et al. (Sun,) studied this question.