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Agonist Receptors and G proteins as Mediators of Platelet Activation

  • Lawrence F. Brass
  • James A. Hoxie
  • Thomas Kieber-Emmons
  • David R. Manning
  • Mortimer Poncz
  • Marilyn Woolkalis
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 344)

Summary

Recent studies have helped to define the earliest events of signal transduction in platelets, particularly those involved in the generation of second messengers. The best-understood of these events are those which involve guanine nucleotide binding regulatory proteins. G proteins are heterotrimers comprised of α, β and γ subunits, each of which can exist in multiple forms. Some, but not all, of the known variants of Gα are substrates for ADP-ribosylation by pertussis toxin, a modification which disrupts the flow of information from receptor to effector. The G proteins that have been identified in platelets to date are Gs, Gi1, Gi2, Gi3, Gz and Gq. Gs and one or more of the Gi family members regulate cAMP formation by adenylylcyclase. Gi may also be responsible for the pertussis toxin-sensitive activation of phospholipase C which occurs when platelets are activated by thrombin. Gq is thought to be responsible for the pertussis toxin-resistant activation of phospholipase C by TxA2. Gz does not have an established role, but has the unique property of being phosphorylated by protein kinase C during platelet activation. Recent efforts to clone the receptors that interact with G proteins in platelets have been successful for epinephrine, thrombin, TxA2 and platelet activating factor. Each of these resembles other G protein-coupled receptors, being comprised of a single polypeptide with 7 transmembrane domains. In the case of thrombin, receptor activation is thought to involve a unique mechanism in which thrombin cleaves its receptor, creating a new N-terminus that can serve as a tethered ligand. Peptides corresponding to the tethered ligand can mimic the effects of thrombin, while antibodies to the same domain inhibit platelet activation. Shortly after activation, thrombin receptors become resistant to re-activation by thrombin. This desensitization, which appears to be due to a combination of proteolysis, phosphorylation and internalization, provides a potential mechanism for limiting the duration of thrombin-initiated signals in platelets.

Keywords

Platelet Activation Human Platelet Pertussis Toxin Platelet Response Thrombin Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • Lawrence F. Brass
    • 1
  • James A. Hoxie
    • 1
  • Thomas Kieber-Emmons
    • 1
  • David R. Manning
    • 1
  • Mortimer Poncz
    • 1
  • Marilyn Woolkalis
    • 1
  1. 1.Departments of Medicine, PathologyPharmacology and Pediatrics of the University of Pennsylvania and the Wistar InstituteUSA

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