Vol. 62, Issue 6, 1356-1363, December 2002

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

Xuechu Zhen, Claudio Torres, Guoping Cai, and Eitan Friedman

Department of Physiology and Pharmacology, City University of New York Medical School, New York, New York

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.