1,2-Diacylglycerols (DA) are potent second messengers formed from the receptor-mediated hydrolysis of membrane phospholipids. DA is an essential cofactor for protein kinase C (PKC) activity. PKC phosphorylates a myriad of target proteins that in smooth muscle cell types may be associated, in part, with sustained contraction and proliferation. Preliminary data in rat glomerular mesangial cells suggest that certian receptor-mediated agonists activate phospholipases linked to specific phospholipids. Specifically, regulatory (arginine vasopressin) and pathophysiological (Platelet-activating factor) vasoconstrictor agonists as well as a proinflammatory cytokine (IL-1) generate DRG from distinct phospholipid sources as a function of time. As individual phospholipid species differ in their sn-1 and sn-2 substituents, receptors coupled to specific phospholipase C activities may generate discrete pools of diradyglycerols (DRG) including diacyl-, alkyl,acyl-, or alkenyl, acyl-glycerol species of various chain lengths and degrees of saturation. DRG is a generic term to describe diglycerides composed of undefined long-chain hydrocarbon substituents. The physiology and biochemistry of these unique DRG pools will be the major focus of this proposal. The major hypothesis to be tested postulates that there is a structural correlation between the species of DRG generated and their regulatory function in smooth muscle cell types. The individual molecular species of DRG generated by AVP, PAF or IL-1 will be documented and correlated with their actions on protein kinase C activity. Alter-native roles for these unique DRG pools will be investigated including modulation of DRG-lipase, kinase, and sphingomyelinase activities and potential generation of eicosanoids, phosphatidic acid, and sphingosine, respectively. Thus, discrete DRG molecular species may determine how distinct receptor-mediated agonists induce diverse physiological events through relatively common regulatory signals. The biochemical information contained in individual species of DRG may allow these molecules to function as key branch points in transmembrane signalling.
|Thibonnier, M; Bayer, A L; Simonson, M S et al. (1991) Multiple signaling pathways of V1-vascular vasopressin receptors of A7r5 cells. Endocrinology 129:2845-56|