L-DOPA reverses the MPTP-induced elevation of the arrestin2 and GRK6 expression and enhanced ERK activation in monkey brain

Neurobiol Dis. 2005 Mar;18(2):323-35. doi: 10.1016/j.nbd.2004.10.005.

Abstract

Dysregulation of dopamine receptors (DARs) is believed to contribute to Parkinson disease (PD) pathology. G protein-coupled receptors (GPCR) undergo desensitization via activation-dependent phosphorylation by G protein-coupled receptor kinases (GRKs) followed by arrestin binding. Using quantitative Western blotting, we detected profound differences in the expression of arrestin2 and GRKs among four experimental groups of nonhuman primates: (1) normal, (2) parkinsonian, (3) parkinsonian treated with levodopa without or (4) with dyskinesia. Arrestin2 and GRK6 expression was significantly elevated in the MPTP-lesioned group in most brain regions; GRK2 was increased in caudal caudate and internal globus pallidus. Neither levodopa-treated group differed significantly from control. The only dyskinesia-specific change was an elevation of GRK3 in the ventral striatum of the dyskinetic group. Changes in arrestin and GRK expression in the MPTP group were accompanied by enhanced ERK activation and elevated total ERK expression, which were also reversed by L-DOPA. The data suggest the involvement of arrestins and GRKs in Parkinson disease pathology and the effects of levodopa treatment.

Publication types

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

MeSH terms

  • Animals
  • Antiparkinson Agents / pharmacology
  • Arrestins / metabolism*
  • Basal Ganglia / drug effects
  • Basal Ganglia / metabolism
  • Basal Ganglia / physiopathology
  • Brain / drug effects*
  • Brain / metabolism
  • Brain / physiopathology
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Disease Models, Animal
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Female
  • G-Protein-Coupled Receptor Kinases
  • Levodopa / pharmacology*
  • Macaca fascicularis
  • Parkinsonian Disorders / drug therapy*
  • Parkinsonian Disorders / metabolism
  • Parkinsonian Disorders / physiopathology
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptors, G-Protein-Coupled / metabolism
  • Up-Regulation / drug effects
  • Up-Regulation / physiology
  • beta-Adrenergic Receptor Kinases

Substances

  • Antiparkinson Agents
  • Arrestins
  • Phosphoproteins
  • Receptors, G-Protein-Coupled
  • Levodopa
  • Protein-Serine-Threonine Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • beta-Adrenergic Receptor Kinases
  • G-Protein-Coupled Receptor Kinases
  • G-protein-coupled receptor kinase 6
  • Extracellular Signal-Regulated MAP Kinases