Sulfonylurea receptors (SUR) are expressed in multiple tissues throughout the body. As early as Day 12 of embryonic development in the mouse, SUR is detected in the pancreas, heart and central nervous system. Post-natally, expression is found in virtually all tissues except liver. In the beta cell of the pancreas, the SUR-1 isoform associates with an inward rectifier K-ATP channel (KIR 6) in a one-to- one stoichiometry, with four subunits of each making up the functional unit. Glucose is metabolized to ATP, which closes the channel, resulting in a membrane potential which opens the voltage-dependent Ca channels. The influx of Ca causes insulin vesicles to undergo exocytosis and release of insulin. The sulfonylurea drugs that are used to treat Type 2 diabetes interact with the SUR-1, close the K-ATP channel and thereby stimulate insulin secretion. To study the regulation of the SUR-1 and K-ATP channel expressed in the beta cell of the pancreas, we utilized the BetaTC3 cells that express high levels of both subunits. Dexamethasone inhibits the steady-state levels of SUR-1 and KIR mRNA in a dose- and time-dependent manner. This effect was not due to mRNA stability, since DRB (an inhibitor of transcription) had no effect on the half-life of mRNA. SUR-1 and KIR are adjacent genes on the mouse and human chromosome and lie within 100 kb of each other. The parallel effect of dexamethasone on the half-life of the mRNA was also seen in the half-life of the protein of each subunit. Thus in the pancreas, SUR-1 and KIR are closely related subunits with similar regulatory elements. To study the role of SUR1 and Kir6.2 in brain, transgenic mice have been created overexpressing these genes in the forebrain under influence of the calcium/calmodulin kinase promoter/enhancer. Additionally, a dominant negative forebrain Kir6.2 transgnic has also been created. These mice are being tested for various neurophysiological and behavioral aspects to determine whether the genes of interest may protect against various nervous tissue insults. - sulfonylurea receptor, neuroprotection, transgenic mice
