Intrastriatal injection of ionomycin profoundly changes motor response to l-DOPA and its underlying molecular mechanisms

Long-term l-DOPA treatment of Parkinson's disease is accompanied with fluctuations of motor responses and l-DOPA-induced dyskinesia (LID). Phosphorylation of the dopamine and c-AMP regulated phosphoprotein of 32 kDa (DARPP-32) plays a role in the pathogenesis of LID, and thus dephosphorylation of this protein by activated calcineurin may help reduce LID. One important activator of calcineurin is the Ca2+ ionophore ionomycin. Here, we investigated whether intrastriatal injection of ionomycin to hemiparkinsonian rats produced changes in l-DOPA responses including LID. We also analyzed the effects of ionomycin on key molecular mediators of LID. Results confirmed our hypothesis that ionomycin could downregulate the phosphorylation of DARPP32 at Thr-34 and reduce LID. Besides, ionomycin decreased two established molecular markers of LID, FosB/ΔFosB and phosphorylated ERK1/2. Ionomycin also decreased the phosphorylation of three main subunits of the NMDA receptor, NR1 phosphorylated at ser896, NR2A phosphorylated at Tyr-1325, and NR2B phosphorylated at Tyr-1472. Furthermore, the anti-LID effect of striatally injected ionomycin was not accompanied by reduction of the antiparkinsonian action of l-DOPA. These data indicate that ionomycin largely interacts with striatal mechanisms that are critical to the l-DOPA motor response highlighting the role of protein dephosphorylation by calcineurin.