The goal of this project is to discover the molecular basis of neurochemical transduction mechanisms, using the pineal gland as a model. Efforts are directed at determining the details of the chemical and ionic components of transmembrane signalling processing and in the neural regulation of gene expression. The most important advances made in the first area were those that have clearly indicated that cAMP and cGMP are regulated by a two receptor mechanism which appears to be focused on the regulation of adenylyl and guanylyl cyclases. One leg of this pathway activates these enzymes via GTP binding regulatory proteins, similar to GS alpha. This leg is controlled by beta-adrenergic or VIP receptors: activation of this leg produces only partial stimulation of cAMP and cGMP accumulation. Activation of the other leg is via alpha 1-adrenergic receptors. This activates protein kinase C which acts, perhaps on the regulatory or catalytic proteins, to increase the activation of adenylyl and guanylyl cyclase. Activation of protein kinase C occurs as a result of an increase in (Ca2+)i and in diacylglycerol production by phospholipase C. In addition, in the regulation cGMP, there appears to be a strong requirement for activation of phospholipase A and for an increase in (Ca2+)i. In the area of the neural control of gene expression, advances have been made in purifying N-acetyltransferase and hydroxyindole-O- methyltransferase, and in isolating cDNA clones coding for these enzymes.
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