Release of a hormone from dense secretory granules in response to an extracellular stimulus requires its de novo synthesis to replace depleted stores. While mass action may account for such maintenance of intracellular stores, a mechanism to sense the number or mass of cytoplasmicgranules and respond appropriately to direct protein biosynthesis has yet to be identified. A growing body of evidence, however, indicates that the same mechanisms that regulate secretion of proteins from storage granules also control the expression of the corresponding genes. Thus,the second messengers involved in stimulus-secretion coupling could also control gene expressionin parallel. Such controls could function at the level of transcription initiation, messenger RNA processing and stability, translation efficiency, or at any point in the biosynthetic pathway.

Our current research focuses on the regulation of renin gene expression. Renin is an enzyme that regulates the formation of angiotensin II, the most potent vasocontrictor known. The rate of renin biosynthesis and release plays an important role in the control of blood pressure. As with many proteins, renin is synthesised as an inactive precursor or "pro" form. In humans about 90% of prorenin is secreted continuously (constitutively) from kidney juxtaglomerular cells as it is synthesized. Only the remaining 10% is sorted to the processing pathway where it is converted to renin that is stored for later release in response to extracellular signals (the so-called "regulated" pathway). Thus sorting to the regulated or constitutive pathways provides an additional control to regulate renin secretion.

Current research strategies employed in our laboratory use hybrid genes containing renin promotesequences that are transfected into reninÐexpressing cells and tested for responsiveness to hormones. Mutagenesis of the renin promoter sequences then permits the identification of sites that mediate hormonal responsiveness. Further characteriztion of the renin promoter sequences examine interactions with transcription factors involved in communicating extracellular signals to the transcriptional machinery.