Modulation of human ether-a-go-go-related K+ (HERG) channel inactivation by Cs+ and K+

Unlike many other native and cloned K+ channels, human ether-a-go-go-related K+ (HERG) channels show significant Cs+ permeability with a P-Cs/P-K (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 midpoint 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.