Prostaglandin endoperoxide/thromboxane A2 receptor desensitization. Cross-talk with adenylate cyclase in human platelets.
Platelet activation by the prostaglandin endoperoxide (PGH2)/thromboxane (Tx) A2 analog, U46619, involves stimulation of phospholipase (PL) C and an increase in intracellular calcium via distinct receptor subtypes. Agents which stimulate adenylate cyclase inhibit platelet function. We demonstrate that PGH2/TxA2 receptor desensitization is associated with enhanced stimulation of platelet cyclic AMP by the prostacyclin analog, iloprost and by forskolin. Sensitization of adenylate cyclase is mediated via the PGH2/TxA2 receptor subtype which activates PLC, as it is blocked by the specific antagonist, GR32191 (Takahara, K., Murray, R., FitzGerald, G. A., and Fitzgerald, D. J. (1990) J. Biol. Chem. 265, 6838-6844). This effect is not observed in platelets desensitized with thrombin or platelet activating factor and is not mediated by protein kinase C. Prior exposure of platelets to platelet activating factor results in much greater desensitization of PGH2/TxA2-induced aggregation (mean 64%) compared with calcium stimulation (mean 18%), consistent with selective heterologous desensitization of the PLC-linked PGH2/TxA2 receptor subtype. Platelet activation by PGH2/TxA2 is a tightly regulated process, involving both homologous desensitization of at least two receptor subtypes and sensitization of the platelet adenylase cyclase system.
Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee 37232.
R
R
Murray
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E
Shipp
G A
GA
FitzGerald
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000262:Adenylyl Cyclases / Q000097:blood*; D000242:Cyclic AMP / Q000097:blood; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D066298:In Vitro Techniques; D010972:Platelet Activating Factor / Q000494:pharmacology; D015539:Platelet Activation; D010974:Platelet Aggregation / Q000187:drug effects; D011449:Prostaglandin Endoperoxides / Q000502:physiology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology; D011982:Receptors, Prostaglandin / Q000502:physiology*; D017482:Receptors, Thromboxane; D013917:Thrombin / Q000494:pharmacology; D013928:Thromboxane A2 / Q000502:physiology*; D010738:Type C Phospholipases / Q000097:blood*
D010972:Platelet Activating Factor; D011449:Prostaglandin Endoperoxides; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000242:Cyclic AMP; D011493:Protein Kinase C; D010738:Type C Phospholipases; D013917:Thrombin; D000262:Adenylyl Cyclases; D016285:Iloprost