Coassembly of K_VLQT1 and minK (IsK) proteins to form cardiac I_KS potassium channel

Abstract

THE slowly activating delayed-rectifier K⁺ current, I_KS, modulates the repolarization of cardiac action potentials. The molecular structure of the I_KS channel is not known, but physiological data indicate that one component of theI_KSchannel is minK (refs 1–6), a 130-amino-acid protein with a single putative transmembrane domain⁷. The size and structure of this protein is such that it is unlikely that minK alone forms functional channels^8,9. We have previously used positional cloning techniques to define a new putative K⁺-channel gene, KVLQT1¹⁰. Mutations in this gene cause long-QT syndrome, an inherited disorder that increases the risk of sudden death from cardiac arrhythmias. Here we show that KVLQT1 encodes a K⁺ channel with biophysical properties unlike other known cardiac currents. We considered that K_VLQT1 might coassemble with another subunit to form func-tional channels in cardiac myocytes. Coexpression of K_VLQT1 with minK induced a current that was almost identical to cardiac I_KS. Therefore, K_VLQT1 is the subunit that coassembles with minK to form I_KS channels and I_KS dysfunction is a cause of cardiac arrhythmia.