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Alternative Splicing and RNA Editing of Insect Sodium Channel Transcripts

Voltage-gated sodium channels are essential for the initiation and propagation of the action potential in the nervous system and other excitable cells. Mammals have nine α-subunit genes which encode nine sodium channel isoforms with different gating properties and different expression patterns in various cell types, tissues, and developmental stages. The diverse gating properties and expression patterns of different isoforms are presumably to accommodate unique physiological requirements in specific neuronal and non-neuronal cells (Goldin 2000; Frank and Catterall 2004). In contrast to mammals, most insects have only a single sodium channel gene (Dong 2010). We are carrying out experiments to understand how insects achieve sodium channel diversity with only one sodium channel gene. So far, our results and results from other groups suggest insects utilize alternative splicing and RNA editing to create the functional diversity of sodium channels.

For example, we were able to identify a total of 69 full-length sodium channel clones (BgNav) from the German cockroach (Blattella germanica), and 64 full-length cDNA clones (DmNav) from Drosophila melanogaster. Functional characterization of those clones in Xenopus oocytes revealed a broad range of channel gating. These sodium channel variants are excellent resources not only for evaluating the functional diversity of alternative splicing and RNA editing, but also for identifying specific sequence features that are critical for sodium channel interaction with various sodium channel neurotoxins, including insecticides (Tan et al., 2002a,b; Song et al. 2004; Liu et al., 2004; Olson et al., 2008; Du et al, 2009c; 2010). We are currently taking advantage of the rich genetic resources and tools in D. melanogaster to study the roles of different sodium channel variants in modulating neuronal excitability and insect toxicology in vivo.

Beside alternative splicing and RNA editing, we are also examining the role of auxiliary subunits of insect sodium channels in modulating sodium channel function. In mammals, the β subunits of mammalian sodium channels play important roles in modulating the expression and gating of mammalian sodium channels. However, there are no orthologs of β subunits in insects. Instead, an unrelated transmembrane protein, TipE in Drosophila melanogaster and its orthologs in other insects, is thought to be a sodium channel auxiliary subunit. There are three to four TipE-homologous genes (TEH1-4) in D. melanogaster and other insect species (Derst et al., 2006). We are investigating how these auxiliary subunits modulate the expression and function of sodium channel variants in Xenopus oocytes and in vivo.