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

Abstract

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 32kDa (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.

• Authors: Chao Han, Shuke Nie, Guiqin Chen, Kai Ma, Nian Xiong, Zhentao Zhang, Yan Xu, Tao Wang, Stella M Papa, Xuebing Cao
• Journal: Neuroscience (Neuroscience) Vol. 340 Pg. 23-33 (01 06 2017) ISSN: 1873-7544 [Electronic] United States
• PMID: 27771532 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Antiparkinson Agents
• Calcium Ionophores
• Dopamine and cAMP-Regulated Phosphoprotein 32
• Fosb protein, rat
• NMDA receptor A1
• NR2B NMDA receptor
• Ppp1r1b protein, rat
• Proto-Oncogene Proteins c-fos
• Receptors, N-Methyl-D-Aspartate
• Glutamic Acid
• Levodopa
• Ionomycin
• Calcineurin
• N-methyl D-aspartate receptor subtype 2A
• Dopamine

Topics

• Animals
• Antiparkinson Agents (adverse effects, pharmacology)
• Calcineurin (metabolism)
• Calcium Ionophores (pharmacology)
• Corpus Striatum (drug effects, metabolism)
• Dopamine (metabolism)
• Dopamine and cAMP-Regulated Phosphoprotein 32 (metabolism)
• Dyskinesia, Drug-Induced (drug therapy, metabolism)
• Glutamic Acid (metabolism)
• Ionomycin (pharmacology)
• Levodopa (adverse effects, pharmacology)
• MAP Kinase Signaling System (drug effects, physiology)
• Male
• Parkinsonian Disorders (drug therapy, metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-fos (metabolism)
• Random Allocation
• Rats, Sprague-Dawley
• Receptors, N-Methyl-D-Aspartate (metabolism)