The overall goal of my research program is to determine the molecular mechanism of insulin action with specific emphasis on Ca2+. Specific emphasis of this proposal is placed upon the roles that Ca2+ and the intracellular Ca2+ effector protein, calmodulin, play in 1) the initial coupling events that occur when insulin binds to its receptor, 2) the relationship of these events to the regulation of other Ca2r homeostatic events in the plasma membrane, 3) their relationship to insulin stimulated glucose and amino acid transport and 4) the mechanism and metabolic significance of insulin's ability to stimulate Ca2+ transport by endoplasmic reticulum.
The specific aims of these investigations include: 1. Characterization of the functional and molecular relationships between the insulin-sensitive (Ca2+ + Mg2+)-ATPase, calmodulin and the insulin receptor in the adipocyte plasma membrane. 2. Determination of the effect of streptozotocin-induced diabetes on (Ca2+ + Mg2+)-ATPase and Ca2+ transport in hepatocyte, erythrocyte and adipocyte plasma membranes. 3. Characterization of other Ca2+ homeostatic events (Na+/Ca2+ exchange and Ca2+ channels) and Ca2+-related ion channels (Ca2+ dependent K+ channels and Ca2+/H+ and Na+/H+ exchange) in adipocyte plasma membranes and determine their relationship to insulin action. 4. Determination of the relationship between Ca2+/calmodulin and insulin action in the regulation of glucose transport and ADP ribosylation. 5. Determination of the mechanism and metabolic significance of insulin in the regulation of Ca2+ transport by adipocyte endoplasmic reticulum. These combined molecular and functional investigations are designed to clearly define the role of Ca2+ and calmodulin in insulin action, and should have considerable overall impact on unravelling the cellular mechanisms responsible for the action of this hormone.
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