Modulation of HERG channel inactivation by external cations.
We investigated the effect of external cations on the permeability characteristics and gating kinetics of the human ether- à- go- go-related gene (HERG) current using the whole-cell patch-clamp technique. Inward HERG currents were recorded on hyperpolarization in 140 mM external Cs(+) and Rb(+), as well as K(+). The permeability ratios of Rb(+) and Cs(+) relative to K(+) were 1.25 and 0.56, respectively. Biphasic outward currents were recorded on depolarization in 140 mM Cs(+) and in Rb(+ )with much smaller amplitude. The voltage dependence of inactivation was affected by external cations, such that the half-inactivation voltage shifted from -69.4+/-3.7 mV in K(+) to -30.7+/-1.6 mV in Cs(+) and to -35.8+/-1.9 mV in Rb(+) ( n=5). The time constants of inactivation were also changed significantly by external cations; tau of inactivation at +40 mV was 16.4+/-2.2 ms in 140 mM K(+), 181+/-20.3 ms in Cs(+), and 94.1+/-7.6 ms in Rb(+) ( n=5). Voltage dependence of activation was not altered significantly. The inhibition of the rapid inactivation mechanism by large cations may suggest that the "foot-in-the-door" model of gating is involved in HERG channel inactivation.
Department of Physiology, Cheju National University College of Medicine, Jeju, Korea.
Jae Boum
JB
Youm
Yung E
YE
Earm
Won-Kyung
WK
Ho
D000818:Animals; D016466:CHO Cells; D027682:Cation Transport Proteins / Q000187:drug effects* / Q000502:physiology*; D002412:Cations / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects* / Q000502:physiology*; D002586:Cesium / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects* / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D012413:Rubidium / Q000494:pharmacology*
D027682:Cation Transport Proteins; D002412:Cations; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D024642:Potassium Channels, Voltage-Gated; D011994:Recombinant Proteins; D002586:Cesium; D012413:Rubidium