Therapeutic implications of endothelin and thrombin G-protein-coupled receptor transactivation of tyrosine and serine/threonine kinase cell surface receptors

J Pharm Pharmacol. 2013 Apr;65(4):465-73. doi: 10.1111/j.2042-7158.2012.01577.x. Epub 2012 Aug 20.

Abstract

Objectives: This review discusses the latest developments in G protein coupled receptor (GPCR) signalling related to the transactivation of cell surface protein kinase receptors and the therapeutic implications.

Key findings: Multiple GPCRs have been known to transactivate protein tyrosine kinase receptors for almost two decades. More recently it has been discovered that GPCRs can also transactivate protein serine/threonine kinase receptors such as that for transforming growth factor (TGF)-β. Using the model of proteoglycan synthesis and glycosaminoglycan elongation in human vascular smooth muscle cells which is a component of an in vitro model of atherosclerosis, the dual tyrosine and serine/threonine kinase receptor transactivation pathways appear to account for all of the response to the agonists, endothelin and thrombin.

Summary: The broadening of the paradigm of GPCR receptor transactivation explains the broad range of activities of these receptors and also the efficacy of GPCR antagonists in cardiovascular therapeutics. Deciphering the mechanisms of transactivation with the aim of identifying a common therapeutic target remains the next challenge.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cardiovascular Agents / pharmacology*
  • Cardiovascular Agents / therapeutic use
  • Cardiovascular Diseases / drug therapy
  • Cardiovascular Diseases / metabolism
  • Drug Design*
  • Endothelin Receptor Antagonists
  • Endothelins / antagonists & inhibitors
  • Endothelins / metabolism
  • Humans
  • Molecular Targeted Therapy
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Receptor Protein-Tyrosine Kinases / agonists
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Receptor-Interacting Protein Serine-Threonine Kinases / chemistry
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Receptors, Cell Surface / agonists
  • Receptors, Cell Surface / antagonists & inhibitors
  • Receptors, Cell Surface / metabolism
  • Receptors, Endothelin / agonists
  • Receptors, Endothelin / metabolism*
  • Receptors, Thrombin / agonists
  • Receptors, Thrombin / antagonists & inhibitors
  • Receptors, Thrombin / metabolism*
  • Signal Transduction / drug effects*
  • Thrombin / antagonists & inhibitors
  • Thrombin / metabolism

Substances

  • Cardiovascular Agents
  • Endothelin Receptor Antagonists
  • Endothelins
  • Protein Kinase Inhibitors
  • Receptors, Cell Surface
  • Receptors, Endothelin
  • Receptors, Thrombin
  • Receptor Protein-Tyrosine Kinases
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Thrombin