Competition of calcified calmodulin N lobe and PIP ₂ to an LQT mutation site in Kv7.1 channel

Significance Voltage-gated potassium 7.1 (Kv7.1) channel and KCNE1 protein coassembly forms the I KS K + current that repolarizes the cardiac action potential, and mutations in Kv7.1 and KCNE1 genes cause cardiac arrhythmias. The proximal Kv7.1 C terminus binds calmodulin and the phospholipid phosphatidylinositol-4,5-bisphosphate (PIP 2 ); however, it is unknown whether their binding sites overlap physically and functionally. Here, we reveal the competition of PIP 2 and the calcified form of the calmodulin N lobe to a previously unidentified site in helix B of the proximal Kv7.1 C terminus. Notably, this site bears a mutation causing a cardiac arrhythmia called the long-QT syndrome. Our results suggest that, after receptor-mediated PIP 2 depletion and increased cytosolic Ca 2+ , calcified calmodulin N lobe interacts with helix B in place of PIP 2 to limit excessive I KS current depression.