The Molecular Biology of Potassium Channels and Mutations that Alter the Selectivity of the Pore

Abstract

Molecular biology and Drosophila genetics have combined to give us an enormous amount of information about K+ channels. Work in many labs has resulted in the cloning of a large family of these channels. Originally cloned in Drosophila, homologs in other species have been isolated as well. Diversity within the family is generated by several mechanisms: six different classes of K+ channel genes, multiple closely related genes within a single class, and alternative RNA splicing within a single gene. Easy and abundant expression of the cloned channels in Xenopus oocytes has promoted structure/function studies. Our lab has concentrated on identifying the pore of the channel and characterizing mutations that alter ion selectivity. Starting with the ShB splicing variant from the Shaker locus, we have identified mutations within a region called H5 that greatly enhance the ability of Rb+ and NH4+ to pass through the channel. This H5 region is highly conserved in all the K+ channel sequences of the family and has an intermediate hydrophobicity. One model is proposed, involving an eight-strand beta-barrel, that could account for the physiological data now in hand. Because of the intrinsic interest of the mechanism of ion permeation, and because of the importance of the pore as a site of pharmacological intervention, elucidating the detailed nature of the pore will be an important area for future study.