HYPOTHALAMIC K ATP CHANNEL--A NEURONAL GLUCOSENSOR?

The long-term goal of this proposal is to examine the regulation of the ATP-sensitive K+ channel located on glucosensor neurons in the ventromedial hypothalamic nucleus (VMN) in health and diabetes. This proposal will test the hypotheses that 1) the K-ATP channel is a major mechanism by which VMN neurons sense and respond to alteration in ambient glucose concentration; 2) generation of intracellular ATP within these neurons with subsequent phosphorylation of the channel via a kinase- mediated mechanism leads to closing of the channel and increased cell firing; 3) pathological changes in glucose metabolism secondary to non- insulin dependent diabetes mellitus (NIDDM) will alter K-ATP channel function. These hypotheses derive from our knowledge concerning the pancreatic beta-cell in which ATP is a critical regulator of K-ATP channel activity and insulin secretion. Since prior studies of the K-ATP channel of VMN neurons were made under non-physiologic conditions, we will utilize whole cell patch clamp techniques to test these hypotheses under conditions which more closely mimic physiological conditions existing in glucosensor neurons.