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© The Rockefeller University Press, 0022-1295/1999//565/ $5.00
Journal of General Physiology, Volume 113, Number 4, 1999

Article

Human Ether-à-go-go–related Gene K+ Channel Gating Probed with Extracellular Ca2+

Evidence for Two Distinct Voltage Sensors



J.P. Johnson, Jr., Franklin M. Mullins, and Paul B. Bennett

From the Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602

Human ether-à-go-go–related gene (HERG) encoded K+ channels were expressed in Chinese hamster ovary (CHO-K1) cells and studied by whole-cell voltage clamp in the presence of varied extracellular Ca2+ concentrations and physiological external K+. Elevation of external Ca2+ from 1.8 to 10 mM resulted in a reduction of whole-cell K+ current amplitude, slowed activation kinetics, and an increased rate of deactivation. The midpoint of the voltage dependence of activation was also shifted +22.3 ± 2.5 mV to more depolarized potentials. In contrast, the kinetics and voltage dependence of channel inactivation were hardly affected by increased extracellular Ca2+. Neither Ca2+ screening of diffuse membrane surface charges nor open channel block could explain these changes. However, selective changes in the voltage-dependent activation, but not inactivation gating, account for the effects of Ca2+ on Human ether-à-go-go–related gene current amplitude and kinetics. The differential effects of extracellular Ca2+ on the activation and inactivation gating indicate that these processes have distinct voltage-sensing mechanisms. Thus, Ca2+ appears to directly interact with externally accessible channel residues to alter the membrane potential detected by the activation voltage sensor, yet Ca2+ binding to this site is ineffective in modifying the inactivation gating machinery.

Key Words: human ether-à-go-go–related gene • potassium ion channel • gating kinetics • membrane surface charge • divalent cation

Address correspondence to Paul B. Bennett, Ph.D., Department of Pharmacology (WP26-265), Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486. Fax: 215-652-0800; E-mail: paul_bennett{at}merck.com

Abbreviations: CHO, Chinese hamster ovary; HERG, human ether-à-go-go–related gene; IKr, delayed rectifier K+ current


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