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 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, expressing SUR1 in the forebrain demonstrated reduced responses to Kainic and a glutamate receptor agonist. They showed fewer epileptic seizures, less mortality and reduced hippocampal neuronal cell death compared with wild-type mice. Thus, SUR1 K+ channels in the brain are protective.
