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Vol. 55, Issue 5, 812-820, May 1999
Program in Pharmacology and Toxicology (J.V.S., A.J.Y.) and
Departments of
Physiology and Pharmacology (A.J.Y.), University of
Arizona, College of Medicine, Tucson Arizona
Kv1.2 and Kv1.5 are two subtypes of voltage-gated potassium channels
expressed in heart that are thought to contribute to phase 1 (ITO) and phase 3 (IK) components of cardiac
action potential repolarization. Although the effect of
decreased pH in prolonging cardiac action potentials is well
documented, the molecular target of acidification has not previously
been determined. We expressed Kv1.2 and Kv1.5 in Xenopus
oocytes to study the effect of acidic and alkaline extracellular pH on
channel function. Using two-electrode voltage clamp and
cellattached patch clamp, we demonstrate that Kv1.5 channels show
enhanced C-type inactivation at acidic pH that is relevant to
pathophysiological conditions. In contrast, homologous Kv1.2 channels
are resistant to acidic pH. Both channel types are insensitive to
alkaline pH. A histidine residue in the third extracellular loop of
Kv1.5 (H452) accounts for the difference in pH sensitivity between the
Kv1.5 and Kv1.2 channels. Mutation of histidine H452 to a glutamine
residue in Kv1.5 yields a channel that no longer shows enhanced
inactivation with acidification. These data provide insight into
mechanisms subserving known pH effects on cellular signaling functions.
Our results demonstrate that H452 in the third extracellular loop of
Kv1.5 plays a role in C-type inactivation, thus expanding the known
complement of protein regions that contribute to the slow
K+ channel inactivation mechanism.
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