Cyclic AMP regulates the HERG K+ channel by dual pathways

Lethal cardiac arrhythmias are a hallmark of the hereditary Long QT syndrom e (LQTS), a disease produced by mutations of cardiac ion channels [1], Ofte n these arrhythmias are stress-induced, suggesting a relationship between ( -beta)adrenergic activation of adenylate cyclase and cAMP-dependent alterat ion of one or more of the ion channels involved in LOTS, Second messengers modulate ion channel activity either by direct interaction or through inter mediary kinases and phosphatases. Here we show that the second messenger cA MP regulates the K+ channel mutated in the LQT2 form of LOTS, HERG [2], bot h directly and indirectly. Activation of cAMP-dependent protein kinase (PKA ) causes phosphorylation of HERG accompanied by a rapid reduction in curren t amplitude, acceleration of voltage-dependent deactivation, and depolarizi ng shift in voltage-dependent activation. In a parallel pathway, cAMP direc tly binds to the HERG protein with the opposing effect of a hyperpolarizing shift in voltage-dependent activation. The summation of cAMP-mediated effe cts is a net diminution of the effective current, but when HERG is complexe d with with the K+ channel accessory proteins MiRP1 or minK, the stimulator y effects of cAMP are favored. These findings provide a direct link between stress and arrhythmia by a unique mechanism where a single second messenge r exerts complex regulation of an ion channel via two distinct pathways.