Altered expression and subcellular distribution of GRK subtypes in the dopamine-depleted rat basal ganglia is not normalized by l-DOPA treatment.
Dysregulation of dopamine (DA) receptors is believed to underlie Parkinson's disease pathology and l-DOPA-induced motor complications. DA receptors are subject to regulation by G protein-coupled receptor kinases (GRKs) and arrestins. DA lesion with 6-hydroxydopamine caused multiple protein- and brain region-specific changes in the expression of GRKs. In the globus pallidus, all four GRK isoforms (GRK2, 3, 5, 6) were reduced in the lesioned hemisphere. In the caudal caudate-putamen (cCPu) three GRK isoforms (GRK2, 3, 6) were decreased by DA depletion. The decrease in GRK proteins in globus pallidus, but not cCPu, was mirrored by reduction in mRNA. GRK3 protein was reduced in the rostral caudate-putamen (rCPu), whereas other isoforms were either unchanged or up-regulated. GRK6 protein and mRNA were up-regulated in rCPu and nucleus accumbens. l-DOPA (25 mg/kg, twice daily for 10 days) failed to reverse changes caused by DA depletion, whereas D(2)/D(3) agonist pergolide (0.25 mg/kg daily for 10 days) restored normal levels of expression of GRK5 and 6. In rCPu, GRK2 protein was increased in most subcellular fractions by l-DOPA but not by DA depletion alone. Similarly, l-DOPA up-regulated arrestin3 in membrane fractions in both regions. GRK5 was down-regulated by l-DOPA in cCPu in the light membrane fraction, where this isoform is the most abundant. The data suggest that alterations in the expression and subcellular distribution of arrestins and GRKs contribute to pathophysiology of Parkinson's disease. Thus, these proteins may be targets for antiparkinsonian therapy.
Ahmed
M Rafiuddin
MR
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Bychkov
Evgeny
E
Gurevich
Vsevolod V
VV
Benovic
Jeffrey L
JL
Gurevich
Eugenia V
EV
D000818:Animals; D019390:Arrestins / Q000378:metabolism; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000378:metabolism; D054770:G-Protein-Coupled Receptor Kinase 3 / Q000235:genetics / Q000378:metabolism; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics / Q000378:metabolism; D054768:G-Protein-Coupled Receptor Kinases / Q000235:genetics* / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D007980:Levodopa / Q000494:pharmacology*; D008474:Medial Forebrain Bundle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010479:Pergolide / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D019390:Arrestins; D015259:Dopamine Agents; D018491:Dopamine Agonists; D010479:Pergolide; D007980:Levodopa; D054770:G-Protein-Coupled Receptor Kinase 3; C496569:Grk2 protein, rat; C517851:Grk3 protein, rat; D054769:G-Protein-Coupled Receptor Kinase 2; D054774:G-Protein-Coupled Receptor Kinase 5; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6; C517897:Grk5 protein, rat; D004298:Dopamine