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Amplification of Diacylglycerol Activation of Protein Kinase C by Cholesterol

Department of Cell Biology and Neuroscience, University of California, Riverside, California

Correspondence: Address reprint requests to Raphael Zidovetski, Tel.: 951-827-5628; E-mail: zidovet{at}mail.ucr.edu; or E-mail: raphael.zidovetzki{at}ucr.edu.

The combined effects of cholesterol, a major cell membrane component, and the lipid second messenger diacylglycerol on the activity of protein kinase C (PK-C) and the structure of phosphatidylcholine/phosphatidylserine bilayers were investigated using specific PK-C assays and ²H NMR. Whereas the classical activation of PK-C was observed as an effect of diacylglycerol, in the absence of this second messenger, cholesterol did not affect PK-C activity. A novel effect of amplified PK-C activation was observed in the presence of both cholesterol and diacylglycerol concentrations within the physiological range of each of these components. ²H NMR results suggest that this phenomenon is due to cholesterol- and diacylglycerol-induced increased propensity of the lipids to adopt nonbilayer phases, effectively destabilizing the bilayer structure. The magnitude of the effect was a function of cholesterol concentration, implying that laterally separated cell membrane domains with distinct cholesterol concentrations have the capacity to differ in their sensitivity to extracellular stimuli.