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

Kv1.2 and Kv1.5 are two subtypes of voltage-gated potassium channels expres sed in heart that are thought to contribute to phase 1 (I-TO) and phase 3 ( I-K) components of cardiac action potential repolarization. Although the ef fect of decreased pH in prolonging cardiac action potentials is well docume nted, the molecular target of acidification has not previously been determi ned. 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-electr ode voltage clamp and cell-attached 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) account s 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 chann el that no longer shows enhanced inactivation with acidification. These dat a provide insight into mechanisms subserving known pH effects on cellular s ignaling functions. Our results demonstrate that H452 in the third extracel lular loop of Kv1.5 plays a role in C-type inactivation, thus expanding the known complement of protein regions that contribute to the slow KC channel inactivation mechanism.