Modulation of human ether-à-go-go-related K+ (HERG) channel inactivation by Cs+ and K+.
Unlike many other native and cloned K+ channels, human ether-à-go-go-related K+ (HERG) channels show significant Cs+ permeability with a PCs/PK (the permeability of Cs+ relative to that of K+) of 0.36 +/- 0.03 (n = 10). Here, we find that raising the concentration of external Cs+ (Cs+o) dramatically slows HERG channel inactivation without affecting activation. Replacement of 5 mM K+o by 135 mM Cs+o increased both inactivation and recovery time constants and shifted the mid-point of the steady-state inactivation curve by 25 mV in the depolarized direction (n = 6, P < 0.01). Raising [Cs+]o also modulated the voltage sensitivity of inactivation gating. With 130 mM Cs+i and 135 mM NMDG+o, the inactivation time constant decreased e-fold per 47.5 +/- 1.1 mV (n = 5), and when 20 mM Cs+ was added to the bath solution, the inactivation time constant decreased e-fold per 20.6 +/- 1.3 mV (n = 5, P < 0.01). A quantitative analysis suggests that Cs+o binds to a site in the pore that is influenced by the transmembrane electrical field, so that Cs+o-induced slowing of HERG inactivation is less prominent at strong depolarizations. K+o has effects that are similar to Cs+o and their effects were additive, suggesting Cs+o and K+o may share a common mechanism of action. The strong effects of Cs+ on inactivation but not on activation highlight the importance of ion and channel interactions during the onset of inactivation in the HERG channel.
Zhang
Shetuan
S
Department of Physiology, University of British Columbia, 2146 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3.
Kehl
Steven J
SJ
Fedida
David
D
D027682:Cation Transport Proteins / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002586:Cesium / Q000494:pharmacology*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D007668:Kidney; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D011188:Potassium / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D014162:Transfection
D027682:Cation Transport Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D002586:Cesium; D011188:Potassium