KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP2) sensitivity of IKs to modulate channel activity

Phosphatidylinositol 4,5-bisphosphate (PIP2) is necessary for the function of various ion channels. The potassium channel, I-Ks, is important for cardiac repolarization and requires PIP2 to activate. Here we show that the auxiliary subunit of I-Ks, KCNE1, increases PIP2 sensitivity 100-fold over channels formed by the pore-forming KCNQ1 subunits alone, which effectively amplifies current because native PIP2 levels in the membrane are insufficient to activate all KCNQ1 channels. A juxtamembranous site in the KCNE1 C terminus is a key structural determinant of PIP2 sensitivity. Long QT syndrome associated mutations of this site lower PIP2 affinity, resulting in reduced current. Application of exogenous PIP2 to these mutants restores wild-type channel activity. These results reveal a vital role of PIP2 for KCNE1 modulation of I-Ks channels that may represent a common mechanism of auxiliary subunit modulation of many ion channels.