Open AccessModulation of human ether-a-go-go-related K+ (HERG) channel inactivation by Cs+ and K+
Author(s) -
Shetuan Zhang,
Steven J. Kehl,
David Fedida
Publication year - 2003
Publication title -
journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2003.039198
Subject(s) - herg , chemistry , gating , biophysics , membrane potential , time constant , potassium channel , biochemistry , biology , engineering , electrical engineering
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.