Molecular Physiology

cAMP Performs a HERG-culean Task

Science's STKE  13 Jun 2000:
Vol. 2000, Issue 36, pp. tw1
DOI: 10.1126/stke.2000.36.tw1

HERG, the pore-forming subunit of the rapidly activating delayed rectifier K+ channel, is regulated by cAMP; however, the mechanism of control remains unknown. Cui et al. show that direct and indirect effects of cAMP regulate activation of the K+ channel in antagonistic ways. cAMP-treated CHO cells expressing HERG yielded decreased K+ current and faster voltage-dependent deactivation. However, treatment of the cells with the PKA inhibitor PKI, plus cAMP, not only abolished the deactivation and current reduction, but actually caused an increase in voltage-dependent activation. The authors demonstrate that PKA can phosphorylate HERG in vitro and that a nucleotide-binding domain within HERG binds cAMP. HERG-expressing CHO cells that express minK or hMiRP1, proteins that complex with HERG in cardiac myocytes, exhibit increased voltage activation and decreased current inhibition in the presence of cAMP. This suggested that minK and hMiRP1 interfere with PKA activity and allow for the PKA-independent effects of cAMP on IKr to dominate over PKA-dependent effects. These findings have implications for patients with cardiac arrhythmias such as long QT syndrome, with defective myocyte repolarization, and suggest new targets for therapy.

Cui, J., Melman, Y., Palma, E., Fishman, G.I., McDonald, T.V. (2000) Cyclic AMP regulates the HERG K+ channel by dual pathways. Curr. Biol. 10: 671-674. [Online Journal]