Inhibition of Protein Tyrosine/Mitogen-Activated Protein Kinase Phosphatase Activity Is Associated with D2 Dopamine Receptor Supersensitivity in a Rat Model of Parkinson's Disease

• Published in: Molecular pharmacology 2002-12, Vol.62 (6), p.1356-1363
• Main Authors: Zhen, Xuechu, Torres, Claudio, Cai, Guoping, Friedman, Eitan
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal - drug effects; Corpus Striatum - enzymology; Disease Models, Animal; Dopamine Agonists - pharmacology; Oxidopamine - pharmacology; Parkinson Disease - enzymology; Parkinson Disease - metabolism; PC12 Cells; Phosphorylation; Protein Tyrosine Phosphatases - antagonists & inhibitors; Protein Tyrosine Phosphatases - metabolism; Quinpirole - pharmacology; Rats; Receptors, Dopamine D2 - metabolism; Sympatholytics - pharmacology; Tyrosine - metabolism; Vanadates - pharmacology
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.62.6.1356

Previous work demonstrated that stimulation of D2 dopamine receptors (D2DRs) in the unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rat enhanced striatal extracellular signal-regulated kinase (ERK) activity ipsilateral to the lesion. The present work was designed to explore the mechanism underlying the activation of ERK in the denervated striatum. Stimulation of D2DR induced a 60% inhibition in protein tyrosine phosphatase (PTP) activity but not in PSP activity in lesioned striata. The D2DR antagonist spiperone blocked quinpirole-elicited PTP inhibition, and the D1 receptor agonist 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (SKF38393) did not inhibit PTP activity, indicating that PTP inhibition is a specific effect mediated by stimulation of D2DR. We further discovered that striatal mitogen-activated protein kinase phosphatase (MKP), a protein phosphatase that is responsible for ERK dephosphorylation, is inhibited in response to D2DR stimulation in 6-OHDA-lesioned rats. More specifically, MKP1 was identified to be the isozyme affected by D2DR stimulation. In PC12 cells that express D2DR, quinpirole elicited no change in PTP or MKP activity, whereas ERK was activated by D2 dopamine receptor stimulation. The results indicate that 6-OHDA-induced striatal denervation leads to abnormal coupling between D2DR and PTP/MKP pathway. Moreover, unilateral inhibition of striatal PTP by an intrastriatal injection of vanadate induced contralateral rotation in control rats in response to D2DR stimulation, thus mimicking the response observed in the unilateral 6-OHDA-lesioned rat. The results indicate that attenuation of the PTP/MKP pathway may be responsible for the development of D2DR supersensitivity.