MOLECULAR NEUROGENETICS OF DROSPHILA POTASSIUM CHANNELS

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Potassium (K+) channels are an exceptionally diverse group of ion channels that are similar in their ability to select for K+ over other ions, but differ in their kinetic, voltage-dependent, pharmacological and single- channel behavior. Due to their prevalence and diversity, tissue-specific distribution of different classes of K+ channels plays a leading role in controlling neuronal activity. Different classes of K+ channels have been shown to contribute significantly to several physiological functions including action potential repolarization, cardiac pacemaking, neuron bursting and learning and memory. This proposal will examine the molecular mechanisms involved in controlling the expression of different K+ channel subtypes and the role these play in generating diverse excitability properties in nerve and muscle. Molecular analysis of the Shaker (Sh) locus of Drosophila melanogaster indicates the Sh encodes a family of functionally distinct A-type K+ channels. Different Sh gene products are expressed in a tissue-specific manner, and phenotypes of Sh alleles suggest a requirement for specific Sh gene products in particular tissues. The effects of indiscriminate Sh gene expression on excitability properties of nerve and muscle will be investigated by electrophysiological analysis of Sh mutant files transformed with Sh cDNAs expressed from a heterologous promoter (heat shock protein 70 gene promoter). Temporal and spatial patterns of Sh gene expression, and the molecular mechanisms underlying these expression patterns, will be examined by histochemical staining for enzymatic activity in flies transformed with hybrid genes in which expression of enzyme reported genes is driven by Sh control elements. Regulatory pathways will be dissected by analysis of other Drosophila leg- shaking mutations that are thought to affect expression of Sh encoded K+ channels. Analysis of Sh is certain to provide novel information about K+ channel regulatory mechanisms that may operate in the nervous system of all organisms.