The goal is to determine the molecular mechanism of insulin action. 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 Ca2+ 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. 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. 3. Determination of the relationship between Ca2+/calmodulin and insulin action in the regulation of glucose transport and ADP ribosylation. 4. 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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