L-DOPA reverses the MPTP-induced elevation of the arrestin2 and GRK6 expression and enhanced ERK activation in monkey brain.
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.
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Basal Gang, CNRS UMR 5543, Université Victor Segalen-Bordeaux 2, 33076 Bordeaux Cedex, France.
Gross
C E
CE
Qin
Li
L
Gurevich
V V
VV
Benovic
J L
JL
Gurevich
E V
EV
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D019390:Arrestins / Q000378:metabolism*; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D054768:G-Protein-Coupled Receptor Kinases; D007980:Levodopa / Q000494:pharmacology*; D008252:Macaca fascicularis; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D051552:beta-Adrenergic Receptor Kinases
D000978:Antiparkinson Agents; D019390:Arrestins; D010750:Phosphoproteins; D043562:Receptors, G-Protein-Coupled; D007980:Levodopa; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6; D048049:Extracellular Signal-Regulated MAP Kinases