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

G protein-coupled receptor kinase 5 (GRK5) is a member of a family of enzym es that phosphorylate activated G protein-coupled receptors (GPCR). To addr ess 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 behavi oral supersensitivity upon challenge with the nonselective muscarinic agoni st oxotremorine. Classical cholinergic responses such as hypothermia, hypoa ctivity, tremor, and salivation were enhanced in GRK5-KO animals. The antin ociceptive effect of oxotremorine was also potentiated and prolonged. Musca rinic receptors in brains from GRK5-KO mice resisted oxotremorine-induced d esensitization, as assessed by oxotremorine-stimulated [S-35]GTP gamma S bi nding. These data demonstrate that elimination of GRK5 results in cholinerg ic supersensitivity and impaired muscarinic receptor desensitization and su ggest that a deficit of GPCR desensitization may be an underlying cause of behavioral supersensitivity.