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J. Gen. Physiol.,
Volume 112, Number 5, November 1, 1998 637-647
From the Department of Physiology, University of Wisconsin-Madison Medical School, Madison, Wisconsin 53706
Abnormalities in repolarization of the cardiac ventricular action potential can lead to life-threatening arrhythmias associated with long QT syndrome. The repolarization process depends upon the gating properties of potassium channels encoded by the human ether-à-go-go-related gene (HERG), especially those governing the
rate of recovery from inactivation and the rate of deactivation. Previous studies have demonstrated that deletion
of the NH2 terminus increases the deactivation rate, but the mechanism by which the NH2 terminus regulates deactivation in wild-type channels has not been elucidated. We tested the hypothesis that the HERG NH2 terminus
slows deactivation by a mechanism similar to N-type inactivation in Shaker channels, where it binds to the internal
mouth of the pore and prevents channel closure. We found that the regulation of deactivation by the HERG NH2
terminus bears similarity to Shaker N-type inactivation in three respects: (a) deletion of the NH2 terminus slows
C-type inactivation; (b) the action of the NH2 terminus is sensitive to elevated concentrations of external K+, as if
its binding along the permeation pathway is disrupted by K+ influx; and (c) N-ethylmaleimide, covalently linked to
an aphenotypic cysteine introduced within the S4-S5 linker, mimics the N deletion phenotype, as if the binding of
the NH2 terminus to its receptor site were hindered. In contrast to N-type inactivation in Shaker, however, there
was no indication that the NH2 terminus blocks the HERG pore. In addition, we discovered that separate domains within the NH2 terminus mediate the slowing of deactivation and the promotion of C-type inactivation. These results suggest that the NH2 terminus stabilizes the open state and, by a separate mechanism, promotes C-type inactivation.
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