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Received January 9, 2003
Accepted after revision February 7, 2003
1 Department of Physiology, University of British Columbia, 2146 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3
* To whom correspondence should be addressed. E-mail: fedida{at}interchange.ubc.ca.
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 35 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.
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