title: The phospholipase C isozymes and their regulation.
abstract: The physiological effects of many extracellular neurotransmitters, hormones, growth factors, and other stimuli are mediated by receptor-promoted activation of phospholipase C (PLC) and consequential activation of inositol lipid signaling pathways. These signaling responses include the classically described conversion of phosphatidylinositol(4,5)P(2) to the Ca(2+)-mobilizing second messenger inositol(1,4,5)P(3) and the protein kinase C-activating second messenger diacylglycerol as well as alterations in membrane association or activity of many proteins that harbor phosphoinositide binding domains. The 13 mammalian PLCs elaborate a minimal catalytic core typified by PLC-d to confer multiple modes of regulation of lipase activity. PLC-b isozymes are activated by Gaq- and Gbg-subunits of heterotrimeric G proteins, and activation of PLC-g isozymes occurs through phosphorylation promoted by receptor and non-receptor tyrosine kinases. PLC-e and certain members of the PLC-b and PLC-g subclasses of isozymes are activated by direct binding of small G proteins of the Ras, Rho, and Rac subfamilies of GTPases. Recent high resolution three dimensional structures together with biochemical studies have illustrated that the X/Y linker region of the catalytic core mediates autoinhibition of most if not all PLC isozymes. Activation occurs as a consequence of removal of this autoinhibition.
authors.affiliation: Department of Pharmacology, University of North Carolina School of Medicine, 27599, Chapel Hill, NC, USA.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Gresset
authors.forename: John
authors.initials: J
authors.lastname: Sondek
authors.forename: T Kendall
authors.initials: TK
authors.lastname: Harden
mesh_terms: D000818:Animals; D004075:Diglycerides / Q000378:metabolism; D004789:Enzyme Activation; D005057:Eukaryotic Cells / Q000166:cytology / Q000201:enzymology*; D005786:Gene Expression Regulation; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007527:Isoenzymes / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D010766:Phosphorylation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015290:Second Messenger Systems; D010738:Type C Phospholipases / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000378:metabolism*
chemical_list: D004075:Diglycerides; D007527:Isoenzymes; D019269:Phosphatidylinositol 4,5-Diphosphate; D015544:Inositol 1,4,5-Trisphosphate; D010738:Type C Phospholipases; D020962:Heterotrimeric GTP-Binding Proteins