INOSITOL-RELATED LIPIDS AND MUSCARINIC CNS ACTIONS

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It has become increasingly apparent that the stimulated labeling of phosphatidate (PA) and phosphatidylinositol (PI), upon addition of muscarinic ligands to various tissues, is a reflection of lipid turnover in which the receptor-ligand interaction initiates the breakdown of inositide, especially of phosphatidylinositol 4,5 bisphosphate (PIP2). Inositol trisphosphate (IP3), the product of PIP2 cleavage, has been implicated as a second messenger. Our laboratory is particularly interested in the CNS muscarinic receptor in nerve endings (synaptosomes). We have chosen as auxiliary models the murine neuroblastoma cell (clone N1E-115) and the avian salt gland (duck), since like the nerve ending preparation, the cells do not engage in exocytotic secretion. In addition to the advantages of studying intact cells which seemingly share a common mechanism, there is the useful technical property that in these cells lipid changes associated with the receptor-ligand response will easily be distinguished from the more gross effects seen in lipid metabolism following exocytotic secretion seen in most other models. Parameters of interest associated with the intracellular response include changes in cyclin GMP and Ca2+. In addition, we hope to reconstruct a broken cell preparation in which the receptor-ligand interaction will directly affect the action of a phospholipase C-type phosphodiesterase which breaks down PIP2 to IP3 and diacylglycerol. A prior suggestion that PIP2 cleavage yields a 1,2-cyclic IP3 derivative (cIP3) will be reinvestigated in view of its possible messenger function. These experiments have relevance, not only in that they may constitute a novel second messenger system, but also that they may explain the therapeutic role of Li+ in affective disorders, since low concentrations of Li+ are known to affect the breakdown of intracellular inositol monophosphate produced from the degradation of the inositol lipids.