Muscarinic supersensitivity and impaired receptor desensitization in G protein-coupled receptor kinase 5-deficient mice

Neuron. 1999 Dec;24(4):1029-36. doi: 10.1016/s0896-6273(00)81048-x.


G protein-coupled receptor kinase 5 (GRK5) is a member of a family of enzymes that phosphorylate activated G protein-coupled receptors (GPCR). To address the physiological importance of GRK5-mediated regulation of GPCRs, mice bearing targeted deletion of the GRK5 gene (GRK5-KO) were generated. GRK5-KO mice exhibited mild spontaneous hypothermia as well as pronounced behavioral supersensitivity upon challenge with the nonselective muscarinic agonist oxotremorine. Classical cholinergic responses such as hypothermia, hypoactivity, tremor, and salivation were enhanced in GRK5-KO animals. The antinociceptive effect of oxotremorine was also potentiated and prolonged. Muscarinic receptors in brains from GRK5-KO mice resisted oxotremorine-induced desensitization, as assessed by oxotremorine-stimulated [5S]GTPgammaS binding. These data demonstrate that elimination of GRK5 results in cholinergic supersensitivity and impaired muscarinic receptor desensitization and suggest that a deficit of GPCR desensitization may be an underlying cause of behavioral supersensitivity.

Publication types

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

MeSH terms

  • Analgesics / pharmacology
  • Animals
  • Behavior, Animal / drug effects
  • Blotting, Western
  • Body Temperature / drug effects
  • Brain Chemistry / drug effects
  • G-Protein-Coupled Receptor Kinase 5
  • GTP-Binding Proteins / metabolism*
  • Guanosine 5'-O-(3-Thiotriphosphate) / pharmacology
  • Mice
  • Mice, Knockout
  • Motor Activity / drug effects
  • Muscarinic Agonists / pharmacology
  • Oxotremorine / pharmacology
  • Pain Measurement / drug effects
  • Protein Serine-Threonine Kinases / deficiency*
  • Protein Serine-Threonine Kinases / genetics*
  • Receptors, Muscarinic / drug effects
  • Receptors, Muscarinic / physiology*
  • Recombination, Genetic


  • Analgesics
  • Muscarinic Agonists
  • Receptors, Muscarinic
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Oxotremorine
  • Protein Serine-Threonine Kinases
  • G-Protein-Coupled Receptor Kinase 5
  • Grk5 protein, mouse
  • GTP-Binding Proteins