Receptor-effector coupling in platelets: roles of guanine nucleotides.
Platelet-activating factor (PAF), which is thought to cause platelet aggregation and degranulation via a receptor-mediated activation of phospholipase C, had no direct action on PGE1-stimulated cyclic AMP formation in intact human platelets, although it caused a GTP and Na+-dependent inhibition of the adenylate cyclase activity of human platelet particulate fractions. Studies with PAF analogues indicated that the receptors mediating this inhibition of adenylate cyclase had structural specificity very similar or identical to that of the receptors mediating platelet aggregation. These results suggest that the PAF receptors linked to the activation of phospholipase C in intact platelets may, in membrane preparations, become coupled to the inhibition of adenylate cyclase via the guanine nucleotide-binding protein, Gi. Studies with permeabilized human platelets that secrete 5-HT on addition of low concentrations of Ca2+ showed that addition of either PAF or a guanine nucleotide decreased the Ca2+ required for secretion. When added together, PAF and GTP promoted secretion synergistically at low Ca2+ concentrations. Enhanced secretion of 5-HT was associated with increased formation of diacylglycerol. These results show that PAF can stimulate phospholipase C by both GTP-dependent and independent mechanisms. In intact human platelets, PAF receptors may interact preferentially with a guanine nucleotide-binding protein that promotes phosphoinositide breakdown by phospholipase C, rather than with Gi.
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000097:blood; D001792:Blood Platelets / Q000502:physiology*; D002118:Calcium / Q000494:pharmacology; D002463:Cell Membrane Permeability; D000242:Cyclic AMP / Q000097:blood; D004075:Diglycerides / Q000097:blood; D004357:Drug Synergism; D019204:GTP-Binding Proteins / Q000494:pharmacology; D006150:Guanine Nucleotides / Q000502:physiology*; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006801:Humans; D010972:Platelet Activating Factor / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D012964:Sodium / Q000494:pharmacology
D000067956:Adenylyl Cyclase Inhibitors; D004075:Diglycerides; D006150:Guanine Nucleotides; D010972:Platelet Activating Factor; D012701:Serotonin; D006160:Guanosine Triphosphate; D012964:Sodium; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D002118:Calcium