Changes in Subcellular Distribution and Phosphorylation of GluR1 in Lesioned Striatum of 6-Hydroxydopamine-Lesioned and l-dopa-Treated Rats
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Recent evidence has linked striatal amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor function to the adverse effects of long-term dopaminergic treatment in Parkinson’s disease. The phosphorylation of AMPA subunit, GluR1, reflects AMPA receptor activity. To determine whether serine phosphorylation of GluR1 subunit by activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) contributes to the process, we examined the effects of unilateral nigrostriatal depletion with 6-hydroxydopamine and subsequent l-dopa treatment on motor responses and phosphorylation states. Three weeks of l-dopa administration to rats shortened the duration of the rotational response. We found a significant reduction in the abundance of both phosphorylated GluR1 at serine-831 site (pGluR1S831) and GluR1 in the cell plasma membrane of lesioned striatum. Chronic treatment of lesioned rats with l-dopa markedly upregulated the phosphorylation of GluR1 in lesioned striatum with a concomitant normalization of the plasma membrane GluR1 abundance, which lasted at least 1 day after withdrawal of chronic l-dopa treatment. Our immunostaining data showed that these changes were confined to parvalbumin-positive neurons where GluR1 subunits are exclusively expressed. Both the altered motor response duration and the degree of pGluR1S831 were attenuated by the intrastriatal administration of CaMKII inhibitor KN-93. These findings suggest that activation of CaMKII contributes to both development and maintenance of motor response duration alterations, through a mechanism that involves an increase in pGluR1S831 within parvalbumin-positive neurons.
KeywordsGluR1 Phosphorylation CaMKII Parvalbumin l-dopa PD
This study was supported by a project sponsored by the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry and the Post-Project of Excellent Young Medical Person of Xihhua Hospital of Shanghai, China.
- 4.Greenamyre JT (2000) New targets for therapy in Parkinson’s disease: pathogenesis and pathophysiology. Neurology 15:67–80Google Scholar
- 23.Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic PressGoogle Scholar
- 42.Stefani A, Pisani A, Bernardi G, Bonci A, Mercuri NB, Stratta F, Calabresi P (1995) The modulation of dopamine receptors in rat striatum. J Neural Transm 45:61–66Google Scholar