I on channels encoded by the human ether-a-go-go-related gene (HERG) give rise to the rapidly activating delayed rectifier K⁺ current (I_Kr), the perturbation of which causes ventricular arrhythmias associated with inherited and acquired long QT syndrome. Electrolyte imbalances, such as reduced serum K⁺ levels (hypokalemia), also trigger these potentially fatal arrhythmias. In this issue of the JCI, Guo et al. report that physiological levels of serum K⁺ are required to maintain normal HERG surface density in HEK 293 cells and I_Kr in rabbit cardiomyocytes. They found that hypokalemia evoked HERG channel ubiquitination, enhanced internalization via endocytosis, and ultimately degradation at the lysosome, thus identifying unbridled turnover as a mechanism of hypokalemia-induced arrhythmia. But too little channel turnover can also cause disease, as suggested by Kruse et al. in a study also in this issue. The authors identified mutations in TRPM4 — a nonselective cation channel — in a large family with progressive familial heart block type I and showed that these mutations prevented channel internalization (see the related articles beginning on pages 2745 and 2737, respectively).