Kv11.1 channels pass the rapid delayed rectifier current (IKr) which plays a specific role in repolarization of the cardiac action potential and in the suppression of arrhythmias caused by premature stimuli. Inherited mutations in Kv11.1 cause long QT syndrome type 2 (LQTS2) and an increased risk of life threatening arrhythmias. Assessing the degree of arrhythmic risk for a LQTS2 mutation requires knowledge of the amount of protein that reaches the membrane and the gating phenotype of the channel, as perturbations to both factors alter the IKr phenotype.
Our aim is to characterize the protein expression level and gating phenotype for all known LQTS2 mutations, and to correlate the combined phenotype with the degree of arrhythmic risk. Here we focus on two Kv11.1 channel mutations that have relatively normal protein expression levels but dramatically altered gating phenotypes. Mutation R56Q exhibits faster deactivation gating, due to disruption of a charge-charge interaction at the interface between two intracellular domains, and thus increases susceptibility to premature beats and arrhythmia. In contrast, mutation T618S results in a severe hyperpolarizing shift in the voltage dependence of inactivation that renders the channel non-conducting at physiological membrane potentials.
Our data demonstrates the importance of assessing both the protein expression levels and gating phenotype of LQTS2 mutations when assessing pro-arrhythmic risk. Furthermore, if LQTS2 mutations with a predominant reduced protein expression phenotype can be rescued by pharmacological chaperones, it will be vital to know whether the expressed channels would have perturbed function, in order to avoid a pro-arrhythmic phenotype.