GAMMA 2 MSH RECEPTORS, CELLULAR SIGNALING , CA2+, AND HYPERTENSION

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Reports have shown that the regulation of cell function occurs as a result of the coupling of cell membrane receptors to the activation of protein kinases associated with the receptor or through changes in the level of second messengers. In preliminary studies, we have identified gamma-2-Melanocyte stimulating hormone (MSH) receptors in regions of the brain that have been associated with the regulation of blood pressure and behavioral function. We have also shown that gamma-2-MSH increases the level of Protein Kinase C (PKC) and decreases the level of cyclic AMP dependent Protein Kinase (PKA) in synaptosomes isolated from the forebrain, midbrain and hindbrain of Sprague Dawley rats. The increase in the activation of PKC suggest that gamma-2-MSH receptor is coupled to PKC in this system. We hypothesize that gamma-2-MSH, a proopiomelanocortin (POMC)-derived peptide with pressor, natriuretic and cardioaccelerator effects, elicits these cardiovascular effects through the activation of specific PKC's and through changes in the level of the second messengers, diacylglycerol (DAG) and inositol l,4,5-trisphosphate (IP3). Therefore, in order to test our hypothesis, we propose to (1) use receptor autoradiographic techniques to locate and quantify the microscopic distribution of gamma-2-MSH receptors in the different parts of the brain of rats in which blood pressure is regulated, (2) investigate ways in which gamma-2-MSH receptor mediated responses are facilitated through the second messengers DAG and IP3 in the regions of the brains associated with blood pressure regulation and identified in #1. This will be done by first measuring the initial basal level of DAG and IP3 and secondly, by measuring changes in the levels of DAG and IP3 following stimulation by gamma-2-MSH in the regions of the brains associated with hypertension. Further, since membrane receptors have been reported to be coupled to the activation of protein kinases, either by activating a protein kinase associated with the receptor, or through changes in the levels of second messengers we also plan to (3) Identify and localize the specific PKC isozyme(s) in the regions of the brain; and determine the activation of the specific isozymes in the presence and absence of gamma-2-MSH.