Ion channels of excitable membranes play a central role in the generation and modulation of electrical and chemical signals within the nervous system of all organisms. Our laboratory uses a genetic and molecular approach to the study the function of ion channels in the nervous system of Drosophila melanogaster. A principle player in the generation and propagation of action potentials in neurons is the voltage-gated sodium channel. The major action potential sodium channel of the Drosophila nervous system is the product of the paralytic (para) locus. para was first identified by mutations which cause rapid and reversible temperature-sensitive (ts) paralysis in adults.

Two post-transcriptional mechanisms which play a role in generating para channel isoforms are alternative splicing and RNA editing of the adenosine-to-inosine type (A-to-I). There are ten known sites of alternative splicing and four RNA editing sites within para transcripts. We are interested in elucidating the mechanisms of alternative-splicing and RNA editing as well as determining the significance of sodium channel post-transcriptional regulatory mechanisms for nervous system function and behavior. For instance, mutations affecting a rare para alternative splice-form specifically affect the process of olfaction.

Our laboratory is also studying gene products which impinge on para regulation. For instance, we have cloned a Drosophila RNA editase, dADAR, and are pursuing genetic and molecular approaches to determine the role of dADAR in RNA editing in general, and para regulation in particular. Also, mutations in the mle RNA helicase cause a reduction in functional sodium channel transcripts through a specific splicing defect. We are currently studying this helicase mutant in order to understand the role of a RNA helicase in gene expression.

Given the central role of sodium channel in neuronal activity, we are also pursuing antisense RNA and RNAi approaches to knocking out sodium channel function in a regulated fashion. Such an approach will allow for a sensitive assay system to abrogate neuronal function in adults without disrupting the normal development of the nervous system.