Abstract
The agonist dependent hydrolysis of membrane phosphoinositides is a major signal transduction pathway in brain (Berridge 1985; Crews et al. 1988a). A variety of receptors including muscarinic cholinergic, α1-adrenergic, serotonergic, and a variety of peptides, couple to phosphoinositide hydrolysis via activation of phospholipase C (Berridge 1985, Gonzales and Crews 1985). Hydrolysis of one of these phosphoinositides, phosphatidylinositol 4,5-bisphosphate [PtdIns(4, 5)P2] results in the formation of 1,2 diacylglycerol (DAG) and inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], both of which appear to have second messenger functions (Batty et al., 1989; Berridge and Irvine, 1989; Rana and Hokin, 1990). DAG remains in the membrane where it can activate protein kinase C (PKC), a family of calcium/phospholipid dependent kinases, that regulate numerous cellular functions and may play a role in neuronal plasticity and neuronal cell death. Ins(1,4,5)P3 is released into the cytoplasm where it binds to specific receptors on the endoplasmic reticulum and releases intracellular Ca2+ into the cytoplasm. Specific phosphomonoesterases can rapidly metabolize Ins(1,4,5)P3 to inositol 1,4-bisphosphate, inositol 4-monophosphate and finally to free inositol via sequential dephosphorylation (Fig. 1). Ins(1,4,5)P3 can be phosphorylated to Ins(1,3,4,5)P4 by a specific Ca2+/calmodulin sensitive 3-kinase (Batty et al., 1985; Irvine et al., 1986). Ins(1,3,4,5)P4 may also be a second messenger involved in a variety of functions including the Ca2+ influx (Irvine et al., 1986), release of intracellular Ca2+ (Gawler et al., 1990) and sequestration of Ca2+ released by Ins(1,4,5)P3 (Hill and Boynton, 1990; Boynton et al., 1990). Ins(1,3,4,5)P4 is dephosphorylated by a 5-phosphatase to inositol 1,3,4-trisphosphate, an inactive isomer. In addition, a variety of cyclic inositol phosphates are produced by the action of phospholipase C on phosphoinositides. The cyclic inositol phosphates accumulate on prolonged agonist stimulation but their cellular functions are not clear (Bansal and Majerus, 1990).
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Kurian, P., Chandler, L.J., Gerber, M., McKinney, M., Miller, J.H., Crews, F.T. (1992). Unique Aspects of Muscarinic Receptor Stimulated Inositol Polyphosphate Formation in Brain: Changes in Senescence. In: Meyer, E.M., Simpkins, J.W., Yamamoto, J., Crews, F.T. (eds) Treatment of Dementias. Advances in Behavioral Biology, vol 40. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-3432-7_27
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DOI: https://doi.org/10.1007/978-1-4615-3432-7_27
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