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Department of Physiology and Biophysics, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298

Correspondence to Gea-Ny Tseng: gtseng{at}vcu.edu

KCNQ1 and KCNE1 (Q1 and E1) associate to form the slow delayed rectifier I_Ks channels in the heart. A short stretch of eight amino acids at the extracellular end of S1 in Q1 (positions 140–147) harbors six arrhythmia-associated mutations. Some of these mutations affect the Q1 channel function only when coexpressed with E1, suggesting that this Q1 region may engage in the interaction with E1 critical for the I_Ks channel function. Identifying the Q1/E1 contact points here may provide new insights into how the I_Ks channel operates. We focus on Q1 position 145 and E1 positions 40–43. Replacing all native cysteine (Cys) in Q1 and introducing Cys into the above Q1 and E1 positions do not significantly perturb the Q1 channel function or Q1/E1 interactions. Immunoblot experiments on COS-7 cells reveal that Q1 145C can form disulfide bonds with E1 40C and 41C, but not E1 42C or 43C. Correspondingly, voltage clamp experiments in oocytes reveal that Q1 145C coexpressed with E1 40C or E1 41C manifests unique gating behavior and DTT sensitivity. Our data suggest that E1 40C and 41C come close to Q1 145C in the activated and resting states, respectively, to allow disulfide bond formation. These data and those in the literature lead us to propose a structural model for the Q1/E1 channel complex, in which E1 is located between S1, S4, and S6 of three separate Q1 subunits. We propose that E1 is not a passive partner of the Q1 channel, but instead can engage in molecular motions during I_Ks gating.

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				L. Restier, L. Cheng, and M. C. Sanguinetti Mechanisms by which atrial fibrillation-associated mutations in the S1 domain of KCNQ1 slow deactivation of IKs channels J. Physiol., September 1, 2008; 586(17): 4179 - 4191. [Abstract] [Full Text] [PDF]

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