Inositol trisphosphate and diacylglycerol as intracellular second messengers in liver.
Receptor occupation by a variety of Ca2+-mobilizing hormones, such as alpha 1-adrenergic agents, vasopressin and angiotensin II, causes a rapid phosphodiesterase-mediated hydrolysis of phosphatidylinositol-4,5-bisphosphate in the plasma membrane with the production of the water soluble compound myo-inositol-1,4,5-trisphosphate (IP3) and the lipophilic molecule 1,2-diacylglycerol (DG). This review summarizes the recent evidence obtained in the liver that defines the roles of these products as intracellular messengers of hormone action. Intracellular Ca2+ mobilization is mediated by IP3, which releases Ca2+ from a subpopulation of the endoplasmic reticulum, resulting in a rapid increase of the cytosolic free Ca2+ concentration ( [Ca2+]i). Further effects of receptor occupancy are inhibition of the plasma membrane Ca2+-ATPase, despite net Ca2+ efflux, and an increased permeability of the plasma membrane to extracellular Ca2+. The activation of the phospholipid-dependent protein kinase C by DG does not alter Ca2+ fluxes across the plasma membrane. In contrast to some secretory cells, a synergism between protein kinase C activation and increased [Ca2+]i is not observed in liver. Activation of protein kinase C profoundly inhibits the response to alpha 1-adrenergic agonists, with only minimal effects on the vasopressin response. It is concluded that in liver the two inositol-lipid messenger systems, IP3 and DG, exert their effects by essentially separate pathways.
Williamson
J R
JR
Cooper
R H
RH
Joseph
S K
SK
Thomas
A P
AP
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D002450:Cell Communication; D002462:Cell Membrane / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D004075:Diglycerides / Q000378:metabolism / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005989:Glycerides / Q000494:pharmacology*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate; D007295:Inositol Phosphates / Q000378:metabolism / Q000494:pharmacology*; D007473:Ion Channels / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D011493:Protein Kinase C; D011494:Protein Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism; D013268:Stimulation, Chemical; D013403:Sugar Phosphates / Q000494:pharmacology*; D014667:Vasopressins / Q000494:pharmacology
C011439:1,2-diacylglycerol; D000316:Adrenergic alpha-Agonists; D004075:Diglycerides; D005989:Glycerides; D007295:Inositol Phosphates; D007473:Ion Channels; D011956:Receptors, Cell Surface; D013403:Sugar Phosphates; D014667:Vasopressins; D000804:Angiotensin II; D010656:Phenylephrine; D015544:Inositol 1,4,5-Trisphosphate; D011494:Protein Kinases; D011493:Protein Kinase C; D002118:Calcium