SUMOylation determines the voltage required to activate cardiac I(Ks) channels.

I(Ks) channels open in response to depolarization of the membrane voltage during the cardiac action potential, passing potassium ions outward to repolarize ventricular myocytes and end each beat. Here, we show that the voltage required to activate I(Ks) channels depends on their covalent modification by small ubiquitin-like modifier (SUMO) proteins. I(Ks) channels are comprised of four KCNQ1 pore-forming subunits, two KCNE1 accessory subunits, and up to four SUMOs, one on Lys(424) of each KCNQ1 subunit. Each SUMO shifts the half-maximal activation voltage (V(1/2)) of I(Ks) ∼ +8 mV, producing a maximal +34-mV shift in neonatal mouse cardiac myocytes or Chinese hamster ovary (CHO) cells expressing the mouse or human subunits. Unexpectedly, channels formed without KCNE1 carry at most two SUMOs despite having four available KCNQ1-Lys(424) sites. SUMOylation of KCNQ1 is KCNE1 dependent and determines the native attributes of cardiac I(Ks) in vivo.