A mutation in the pore region of HERG K+ channels expressed in Xenopus oocytes reduces rectification by shifting the voltage dependence of inactivation

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Abstract
1 The effects of a mutation in the human ether-a-go-go-related gene (HERG) (Ser631 to Ala, S631A) on the voltage- and extracellular [K+] dependence of inactivation were studied in Xenopus oocytes using two microelectrode and single channel voltage-clamp techniques. 2 The voltage required for half-inactivation of S631A HERG was 102 mV more positive than for wild-type (WT)-HERG, resulting in reduced rectification of the steady-state current-voltage relationship. In contrast, the voltage dependence of channel activation was not altered by the S631A mutation. These findings indicate that inactivation of HERG channels is not linked to activation. 3 Rectification of whole-cell S631A HERG current was caused by a voltage-dependent reduction in open probability, and inward rectification of the current-voltage relationship of single channels. 4 Elevation of extracellular [K+] from 2 to 20 mm shifted the half-point for inactivation by +20 mV for WT-HERG, and +25 mV for S631A HERG. Thus, elevated [K+]o and the S631A mutation affect HERG inactivation by different mechanisms. 5 The S631A mutation altered the ion translocation rate of HERG channels. The single channel conductance (γ) of S631A HERG was 20 pS between -40 and-100 mV, and 6.0 pS between +40 and +100 mV (120 mm extracellular K+). This compares to a γ of 12.1 and 5.1 pS for WT-HERG channels under the same conditions.