Abstract 482 Endocrinology & Diabetes III Platform, Sunday, 5/2

ATP-sensitive potassium channels (KATP) serve as a vital link between cellular metabolism and membrane electrical activity in excitable cells, including pancreatic islets, and cardiac and skeletal muscle. In mammalian systems, it has been demonstrated that regulated KATP channel activity requires functional sulfonylurea receptor and inward rectifier subunits. Current models of KATP support that the SUR subunit confers sensitivity to channel regulators while the Kir6.2 inward rectifier subunit forms the channel pore. Using a genetic approach we have previously demonstrated that autosomal recessive congenital hyperinsulinism, a disorder of unregulated insulin secretion and hypoglycemia, is associated with loss of function mutations of either subunit of the pancreatic islet KATP. We chose to study Drosophila, a proven model system for the isolation and study of ion channels, as a means of gaining further insight into the structure and function of the KATP channel. An approach based on computer searching of the EST database was used to isolate the Drosphila homolog of the sulfonylurea receptor, which we have termed Dsur. The full-length Dsur has a predicted molecular weight of 241,858 daltons, and structural features characteristic of the ABC transporter family. Functional conservation of KATP channel activity was demonstrated by measurement of whole cell currents Xenopus oocytes expressing Dsur. The expression pattern of Dsur was determined by in situ hybridization of Drosophila embryos using a specific cDNA probe. Specific embryonic expression was present beginning at stage 10 in the dorsal vessel, the Drosophila homolog of the heart and circulatory system, and beginning at stage 15 in the tracheal system (including tracheal pits, tree, and placodes). Dsur message was also present in the posterior spiracles and salivary glands. These data reveal conservation of KATP channels in lower organisms and provides the necessary tools to explore multiple questions related to the mechanism of regulation of the SUR gene.