CONTROL OF MEMBRANE ACTIVITY BY NEUROTRANSMITTERS

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In many tissues, receptor-occupancy by neurotransmitters and hormones triggers the hydrolysis of phosphatidylinositol 4,5-bisphosphate in the plasma membrane of the cell. This appears to be a signal transmission system which involves the generation of two putative second messengers - myo-inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DG). This study examines aspects of the mechanism and function of this system. Specific aims include studies of: 1. High-affinity binding sites for IP3 in endoplasmic reticular membranes. 2. The properties of purified phosphatidylinositol synthase, and factors which regulate its activity. 3. The possible role of IP3 and/or DG in a cascade mechanism for the further production of DG by hydrolysis of phosphatidylinositol in endoplasmic reticular membranes. 4. Roles of IP3 and DG as second messengers for the triggering of tissue-specific, biosynthetic, adaptive responses to acetylcholine. Responses to be examined are the synthesis of export protein (digestive enzymes) in the pancreas acinar cell, and the synthesis of the plasma membrane enzyme, NaK-ATPase, in the avian salt gland cell. 5. The effects of treatment with lithium salts in vivo on the phosphoinositide signal transmission system in mouse brain and pancreas, and on end responses to acetylcholine (enzyme secretion and protein synthesis) in the pancreas. The methodology includes: synthesis of radiophotoaffinity compounds; isolation of enzymes; incubation of subcellular membrane fractions, dispersed cell preparations, and tissue slices; preparative and analytical chromatographic techniques. The results from these experiments will further an understanding of the phosphoinositide signal transmission system, and of the role of this system in the induction of the biosynthetic, adaptive changes which occur in response to neurotransmitters and hormones in the nervous system and elsewhere. They will also contribute to an understanding of the actions of lithium salts.