Activation of protein kinase C by phosphatidylinositol 4,5-bisphosphate: possible involvement in Na+/H+ antiport down-regulation and cell proliferation.
Phosphatidylinositol 4,5-bisphosphate (PIP2) as well as diacylglycerol (DG) activate protein kinase C (PKC) in the presence of calcium and phosphatidylserine. The pH at half-activation (pK) is 6.2 for DG.PKC and 7.7 for PIP2.PKC. Since the second monophosphate proton in position 5 of the PIP2 inositol (i.e., the last ionizable proton) has a pK of 7.7 (Van Paridon et al., (1986) Biochim. Biophys. Acta. 877, 216), the active effector is a fully deprotonated PIP2. Activation of PKC by PIP2 thus may follow intracellular alkalinization and be tied to the down-regulation of the Na+/H+ antiport mechanism. Since alkalinization is obligatory for cell proliferation, PIP2(5-).Ca.PKC may also be the gate that opens the pathways toward this and connected cellular reactions. A PIP2 analog in which inositol carbons 2-4 and the 4-phosphate have been removed, 1-phosphatidyl-rac-glycerol-3-phosphate (PGP), is completely inactive as PKC effector; this suggests that both 4-and 5-phosphate are engaged in the PIP2(5-).Ca.PKC complex. A model of the activated kinase takes this into account.
Chauhan
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Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314.
Chauhan
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Brockerhoff
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D000818:Animals; D001921:Brain / Q000201:enzymology; D002352:Carrier Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D006706:Homeostasis; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008954:Models, Biological; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017923:Sodium-Hydrogen Exchangers
D002352:Carrier Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols; D017923:Sodium-Hydrogen Exchangers; D011493:Protein Kinase C