Functional Analysis of a Mouse Brain Elk-Type K+Channel

Abstract

Members of the Ether à go-go (Eag) K⁺channel subfamilies Eag, Erg, and Elk are widely expressed in the nervous system, but their neural functionsin vivoremain largely unknown. The biophysical properties of channels from the Eag and Erg subfamilies have been described, and based on their characteristic features and expression patterns, Erg channels have been associated with native currents in the heart. Little is known about the properties of channels from the Elk subfamily. We have identified a mouse gene,Melk2, that encodes a predicted polypeptide with 48% amino acid identity toDrosophilaElk but only 40 and 36% identity with mouse Erg (Merg) and Eag (Meag), respectively.Melk2RNA appears to be expressed at high levels only in brain tissue. Functional expression ofMelk2inXenopusoocytes reveals large, transient peaks of current at the onset of depolarization. Like Meag currents, Melk2 currents activate relatively quickly, but they lack the nonsuperimposable Cole–Moore shift characteristic of the Eag subfamily. Melk2 currents are insensitive to E-4031, a class III antiarrhythmic compound that blocks the Human Ether-à-go-go-Related Gene (HERG) channel and its counterpart in native tissues, I_Kr. Melk2 channels exhibit inward rectification because of a fast C-type inactivation mechanism, but the slower rate of inactivation and the faster rate of activation results in less inward rectification than that observed in HERG channels. This characterization of Melk currents should aid in identification of native counterparts to the Elk subfamily of channels in the nervous system.