Novel mechanisms for feedback regulation of phospholipase C-beta activity.
The receptor-regulated phospholipase C-beta (PLC-beta) signaling pathway is an important component in a network of signaling cascades that regulate cell function. PLC-beta signaling has been implicated in the regulation of cardiovascular function and neuronal plasticity. The Gq family of G proteins mediate receptor stimulation of PLC-beta activity at the plasma membrane. Mitogens stimulate the activity of a nuclear pool of PLC-beta. Stimulation of PLC-beta activity results in the rapid hydrolysis of phosphatidylinositol-4,5-bisphosphate, with production of inositol-1,4,5-trisphosphate and diacylglycerol, intracellular mediators that increase intracellular Ca2+ levels and activate protein kinase C activity, respectively. Diacylglycerol kinase converts diacylglycerol to phosphatidic acid, a newly emerging intracellular mediator of hormone action that targets a number of signaling proteins. Activation of the Gq linked PLC-beta signaling pathway can also generate additional signaling lipids, including phosphatidylinositol-3-phosphate and phosphatidylinositol-3,4,5-trisphosphate, which regulate the activity and/or localization of a number of proteins. Novel feedback mechanisms, directed at the level of Gq and PLC-beta, have been identified. PLC-beta and regulators of G protein signaling (RGS) function as GTPase-activating proteins on Gq to control the amplitude and duration of stimulation. Protein kinases phosphorylate and regulate the activation of specific PLC-beta isoforms. Phosphatidic acid regulates PLC-beta1 activity and stimulation of PLC-beta1 activity by G proteins. These feedback mechanisms coordinate receptor signaling and cell activation. Feedback mechanisms constitute possible targets for pharmacological intervention in the treatment of disease.
Litosch
Irene
I
Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, Florida 33101, USA. ilitosch@med.miami.edu
D000818:Animals; D002462:Cell Membrane / Q000201:enzymology; D004075:Diglycerides / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D008957:Models, Genetic; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D054799:Phospholipase C beta; D011493:Protein Kinase C / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism / Q000502:physiology*
D004075:Diglycerides; D007527:Isoenzymes; D019269:Phosphatidylinositol 4,5-Diphosphate; D011956:Receptors, Cell Surface; D015544:Inositol 1,4,5-Trisphosphate; D011493:Protein Kinase C; D010738:Type C Phospholipases; C518033:PLCB1 protein, human; D054799:Phospholipase C beta