Functional and Pharmacological Characterization of the Cockroach Voltage-Gated Sodium Channel

Michigan State University, East Lansing MI

Investigators

Abstract

Voltage-gated sodium channels are essential for generation and propagation of electrical impulses in the nervous system and other excitable cells. There are at least ten voltage-gated sodium channel genes in mammals, but only one sodium channel gene in insects. How do insects achieve sodium channel diversity required for fulfilling different roles in different tissues and cell types? Why are some neurotoxins, including pyrethroids (a widely used class of insecticides) and insect-selective scorpion toxins, are more toxic to insects than to mammals? The research proposed by Dr. Dong is aimed at answering these questions. Dr. Dong's laboratory has isolated more than twenty naturally occurring variants of the German cockroach sodium channel. The functional properties of these sodium channel variants will be characterized in the Xenopus oocyte, which is a widely used in vitro functional expression system for ion channels. Based on the preliminary results from Dr. Dong's study, the functional diversity of the German cockroach sodium channel appears to be achieved by modification of the same sodium channel gene transcript via two cellular processes called alternative splicing and RNA editing. Variation in alternative splicing and RNA editing can result in changes in the structure and function of a gene product. Dr. Dong will examine the role of these two cellular processes in generating functional diversity of the German cockroach sodium channel. They will also determine the exact amino acid residues in the German cockroach sodium channel protein that are critical for the selective toxicity of neurotoxins to insect and mammalian sodium channels will be identified. Successful completion of this study may yield the first comprehensive picture of how alternative splicing and RNA editing enables a single gene to generate functionally and pharmacologically diverse sodium channels in insects. Elucidation of the structural basis of functional and pharmacologically diversity will provide valuable information for our better understanding of the structure and function of sodium channels. One postdoctoral associate will gain training in molecular biology, electrophysiology, and toxin pharmacology.