b-adrenergic modulation of cardiac potassium currents controls ventricular action potential duration (APD) at faster heart rates. HERG (KCNH2) gene mutations are associated with congenital long-QT syndrome (LQT2) and affect IKr activity, a key determinant in ventricular repolarization.

In LQT2 families, we identified three novel heterozygous C- terminal HERG mutations (G965X, R1014PfsX39, V1038AfsX21). When expressed in CHO cells, the mutants produced functional HERG channels with normal kinetic properties. Upon co-expression with 14-3-3e - a protein assosciated with protein kinase A (PKA)-dependent HERG channel activation, mutant channels still bound 14-3-3e but did not respond with a hyperpolarizing shift in voltage dependence as seen in wild-type channels. Co-expression experiments of wild- type and mutant channels revealed dominantnegative behavior of all three HERG mutations. Simulations of the experimentally obtained results of PKA-dependent HERG channel activation suggested an impaired ability of mutant cardiac myocytes to respond to a triggered event or an ectopic beat. In summary, the attenuated functional effects of 14-3-3e on C-terminally truncated HERG channels demonstrate the physiological importance of coupling b-adrenergic stimulation and HERG channel activity.