title: 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: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors: Chao
authors: C
authors: Han
authors: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
authors: Shuke
authors: S
authors: Nie
authors: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors: Guiqin
authors: G
authors: Chen
authors: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors: Kai
authors: K
authors: Ma
authors: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors: Nian
authors: N
authors: Xiong
authors: Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
authors: Zhentao
authors: Z
authors: Zhang
authors: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: xuyanwxf@126.com.
authors: Yan
authors: Y
authors: Xu
authors: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors: Tao
authors: T
authors: Wang
authors: Yerkes National Primate Research Center, Department of Neurology, Emory University School of Medicine, Atlanta, GA 30329, USA.
authors: Stella M
authors: SM
authors: Papa
authors: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: caoxuebing@126.com.
authors: Xuebing
authors: X
authors: Cao
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000494:pharmacology*; D019703:Calcineurin / Q000378:metabolism; D061207:Calcium Ionophores / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology*; D007980:Levodopa / Q000009:adverse effects* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D019703:Calcineurin; D061207:Calcium Ionophores; D004298:Dopamine; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D018698:Glutamic Acid; D015759:Ionomycin; D007980:Levodopa; D016760:Proto-Oncogene Proteins c-fos; D016194:Receptors, N-Methyl-D-Aspartate; C483820:Fosb protein, rat; C121001:NR2B NMDA receptor; C497930:Ppp1r1b protein, rat
keywords: DARPP-32; NMDA; dyskinesia; ionomycin; l-DOPA