Voltage-gated Potassium Channel Inhibitors

Abstract

Forty years have transpired since tetraethylammonium was first used to selectively inhibit the potassiuin conductance in squid axons. Since then, a large body of work has emerged describing inhibitors of voltage-gated potassium currents in a variety of cells. The advent of molecular cloning techniques and the cloning of the potassium channel encoded by the Shaker locus in Drosophila has enabled detailed structure­ function studies of several potassium channel subunits. These breakthroughs have also recently enabled studies of the "toxinology" and pharmacology of specific potassium channel subunits expressed heterologously in Xenopus oocytes and other cells. Here we describe the results of some of those efforts, focusing in particular on our work with four members of the Shaker subfamily of potassium channel a-subunits: Kvl.1 through Kvl.4. These subunits are expressed in the central nervous system and other tissues of rodents, and are highly homologous to corresponding subunits expressed in humans. We provide a profile of potency and selectivity for.five snake dendrotoxins as well as several scorpion toxins for these potassium channel subunits expressed in Xenopus oocytes. We also provide similar data for four other peptide toxins and several nonpeptide compounds that had previously been shown to inhibit potassium currents. We discuss several potential clinical applications of potassium channel inhibitors, including demyelinating diseases such as multiple sclerosis, immunosuppression, cardiac arrhythmias, neurodegenerative and psychiatric diseases. Further progress will require, among other things, a greater understanding of the expression patterns of potassium channel subunits in the CNS and elsewhere as well as knowledge of the specific subunit composition of heteromultimeric channels.