Modulation of the IK S channel by PIP 2 requires two binding sites per monomer

Abstract The phosphatidyl-inositol-4,5-bisphosphate (PIP 2 ) lipid has been shown to be crucial for the coupling between the voltage sensor and the pore of the potassium voltage-gated K V 7 channel family, especially the K V 7.1 channel. The latter, expressed in the myocardium membrane is complexed with its auxiliary subunits, KCNE1 to generate the so-called IK S current. We present here molecular models of transmembrane domain of this complex in its three known states, namely the Resting/Closed (RC), the Intermediate/Closed (IC), and the Activated/Open (AO), robustness of which is assessed by agreement with a range of biophysical data. Molecular Dynamics (MD) simulations of these models embedded in a lipid bilayer including phosphatidyl-inositol-4,5-bisphosphate (PIP 2 ) lipids show that in presence of KCNE1, two PIP 2 lipids are necessary to stabilize each state. The simulations also show that KCNE1 interacts with both PIP 2 binding sites, forming a tourniquet around the pore and preventing its opening. The present investigation provides therefore key molecular elements that govern the role of PIP 2 in KCNE1 modulation of IK S channels, possibly a common mechanism by which auxiliary KCNE subunits might modulate a variety of other ion channels.