Dual mechanisms of platelet hormone receptor desensitization. Differential importance between agonists of protein kinase C-dependent and -independent pathways.
Several different agonists, among them alpha-thrombin, platelet-activating factor, vasopressin, thromboxane A2, and endoperoxides, activate platelets to aggregate and secrete granular contents. Each of these agents is thought to act by inducing the turnover of inositol phospholipids and generating the second messenger molecules inositol 1,4,5-trisphosphate and 1,2-diacylglycerol. However, within minutes, the action of these agonists desensitizes. We have studied the characteristics of this desensitization process for the agonists mentioned above in an attempt to clarify the mechanisms involved. Our results show that two different pathways of desensitization exist, one that is mediated by protein kinase C and another that is independent of this enzyme. In addition, the contribution of these pathways to desensitization differs for the agonists studied. Our data suggest that partial agonists and strong agonists differ in the rate at which the primary response is desensitized rather than in their ability to couple to phospholipase C.
Crouch
M F
MF
Department of Molecular Biology, Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709.
Lapetina
E G
EG
D001792:Blood Platelets / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism; D002118:Calcium / Q000097:blood; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D010712:Phosphatidic Acids / Q000097:blood; D010743:Phospholipids / Q000097:blood; D010766:Phosphorylation; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011493:Protein Kinase C / Q000097:blood*; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism*; D015290:Second Messenger Systems; D013917:Thrombin / Q000502:physiology; D014667:Vasopressins / Q000494:pharmacology
D001798:Blood Proteins; D010712:Phosphatidic Acids; D010743:Phospholipids; D011450:Prostaglandin Endoperoxides, Synthetic; D011955:Receptors, Drug; D014667:Vasopressins; C028429:U 44069; D011493:Protein Kinase C; D013917:Thrombin; D002118:Calcium; D004837:Epinephrine