Chromogranin A (CgA) is the major soluble protein in the core of catecholamine storage vesicles. It is coreleased by exocytosis along with catecholamines from storage vesicles in adrenal medulla and sympathetic axons, and its corelease has been used to document exocytosis as the mode of physiologic catecholamine release in experimental animals and in humans. Its functions may include binding of calcium and catecholamines within the catecholamine storage vesicle core, or generation of biologically active peptides such as pancreastatin. Recently, we have noted overexpression of adrenal medullary and plasma CgA in genetic (hereditary) hypertension - both rodent (the spontaneously hypertensive rat; SHR) and human. The synthesis, storage and release of CgA seem to be augmented in the SHR. The data suggest that overexpression of CgA is heritable in both rodent and human genetic hypertension. Since both human essential and rodent (SHR) hypertension are at least in part heritable, it is important to look for alterations in gene expression to understand the pathogenesis of hypertension. The overproduction of CgA suggests increased CgA gene expression (perhaps at the transcriptional level) in hereditary hypertension. Thus, CgA provides an ideal """"""""window"""""""" for examining the involvement of the genome in hereditary hypertension. We have recently isolated and mapped the rodent CgA gene from mouse and rat cosmid genomic libraries. We have determined the gene's intron/exon structure and the sequence of its 5' regulatory region, and have established its functional promoter/enhancer region by transfection and expression of reporter constructs. Thus, we are poised to dissect apart elements of this gene's transcriptional control region likely to be activated in hypertension. In addition, knowledge of control of this catecholaminergic protein's biosynthesis will give us clues to how the sympathochromaffin phenotype is maintained by the genome within such cells, and how gene expression is activated to govern secretion from chromaffin cells and sympathetic axons. The proposed experiments are designed to characterize the transcriptional control region of the CgA gene and the overexpression of CgA in rodent genetic hypertension, and to identify how the genome of hypertensive organisms is activated to yield this overexpression. Furthermore, we will gain understanding of how the nucleus controls secretory protein synthesis in the sympathochromaffin system.
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