Differential sensitivity of voltage-gated potassium channels Kv1.5 and Kv1.2 to acidic pH and molecular identification of pH sensor

Mol Pharmacol. 1999 May;55(5):812-20.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Histidine / metabolism*
  • Hydrogen-Ion Concentration*
  • Kv1.2 Potassium Channel
  • Kv1.5 Potassium Channel
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Oocytes / metabolism
  • Potassium Channels / genetics
  • Potassium Channels / metabolism*
  • Potassium Channels, Voltage-Gated*
  • Sequence Homology, Amino Acid
  • Xenopus laevis

Substances

  • Kv1.2 Potassium Channel
  • Kv1.5 Potassium Channel
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • Histidine