In addition to promoting overall-bodily growth through the actions of the insulin-like growth factors, GH acts directly on terminally differentiated cells in adipose tissue, muscle, liver, and pancreatic islets to regulate energy metabolism. The effects on muscle and adipose tissue are complex and include insulin-like stimulation in GH deprived tissues followed by induction of refractoriness to further stimulation in this mode and by such contra insulin actions as acceleration of lipolysis and antagonism of glucose metabolism. These 3 distinct actions appear to result from separate hormone-receptor interactions. Available information on the GH receptor cannot account for such multiple interactions, and little is known of how the GH receptor signals altered cellular activity. The GH receptor gene is complex, and at least 2 isoforms of receptor protein are expressed through alternate splicing of its mRNA in adipocytes, liver, and probably other tissues. One goal of the proposed studies is to evaluate the hypothesis that different isoforms of the GH receptor mediate different classes of response in adipocytes. We will determine whether additional isoforms are expressed in adipocytes, whether they are subunits of larger receptor complexes, whether they are independently regulated, whether different isoforms or complexes can be associated with particular responses and whether receptors realign, cluster or cap on the cell surface in response to GH. Another goal is to explore the early consequences of GH-receptor interaction in an effort to define the mechanisms of signal transduction. To this end we will study the interactions of a mutated GH which binds to the receptor, but fails to signal and acts instead as a competitive antagonist of GH. We will continue our studies of the newly discovered actions of GH to increase intracellular calcium concentrations, and, in particular, will focus on the mechanisms that underlie this earliest known expression of GH-receptor interaction. Accomplishment of these goals will require application of biochemical and molecular biological approaches as well as digital imaging microscopy. These studies should provide fundamental insights into the mechanisms by which GH modulates the metabolic behavior of differentiated cells and coordinates their activities in support of the overall energy balance of the organism.
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