title: Hormone effects on cellular Ca2+ fluxes.
abstract: The involvement of inositol lipid metabolism in agonist-mediated Ca2+ signaling by Ins 1,4,5-P3 has become firmly established. Recent advances have led to a better understanding of the proteins associated with signal transduction in the plasma membrane. A number of specific receptors (G proteins, phospholipases and inositol lipid kinases) have now been purified and characterized. An Ins 1,4,5-P3 receptor has also been purified which is presumably involved in mediating Ca2+ efflux from intracellular stores. The morphological site of the hormone-sensitive Ca2+ pool has been tentatively identified as discrete, specialized intracellular structures (calciosomes), but further studies are required to demonstrate that these contain Ins 1,4,5-P3-gated Ca2+ channels and their possible functional relationship to the plasma membrane. Receptor occupancy by Ca2+ mobilizing agonists also stimulates Ca2+ entry into the cell, but the mechanism for activation of voltage insensitive Ca2+ channels and the possible involvement of Ins 1,4,5-P3, Ins 1,3,4,5-P4 and/or G proteins in this process has not been established. The Ca2+ signaling pathway is subject to multisite feedback regulation by Ca2+ itself and by a diacylglycerol-mediated activation of protein kinase C. Potential sites for Ca2+ interaction are displacement of Ins 1,4,5-P3 from its receptor by a Ca2+-dependent mechanism, promotion of Ins 1,3,4,5-P4 formation by the Ca2+/calmodulin-regulated Ins 1,4,5-P3 3-kinase, and efflux of Ca2+ from the cell or sequestration into intracellular Ca2+ stores by Ca2+/calmodulin-regulated Ca2+-ATPases. Protein kinase C activation potentially affects the rate of generation of Ins 1,4,5-P3 by negative feedback to the receptor-G protein-phospholipase C transduction system and possibly also the rate of Ins 1,4,5-P3 degradation by activation of an inositol polyphosphate 5-phosphomonoesterase. It may also attenuate the Ca2+ transient directly by increasing the activity of Ca2+-ATPases associated with the plasma membrane and the endoplasmic reticulum. Cell-to-cell heterogeneity in the relative control strengths of these different mechanisms may explain the differences in the Ca2+ signal in different tissues and even in different cells within a population. The ability of Ca2+ and protein kinase C to provide negative feedback at various points in the signal transduction pathway suggests that a complex mechanism involving multiple feedback loops is likely to regulate the generation of Ca2+ oscillations seen in some cells.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia 19104.
authors.forename: J R
authors.initials: JR
authors.lastname: Williamson
authors.forename: J R
authors.initials: JR
authors.lastname: Monck
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation; D005110:Extracellular Space / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000502:physiology; D006728:Hormones / Q000502:physiology*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate; D007295:Inositol Phosphates / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D007425:Intracellular Membranes / Q000378:metabolism*; D010740:Phospholipases / Q000378:metabolism
chemical_list: D006728:Hormones; D007295:Inositol Phosphates; D015544:Inositol 1,4,5-Trisphosphate; D010740:Phospholipases; D019204:GTP-Binding Proteins; D002118:Calcium