Roles of Ca(2+)/calmodulin-dependent protein kinase II in subcellular expression of striatal N-methyl-D-aspartate receptors in l-3, 4-dihydroxyphenylalanine-induced dyskinetic rats.
BACKGROUND
The role of N-Methyl-D-aspartate (NMDA) receptors is critical to the development of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in Parkinson's disease (PD). Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is thought to regulate the expression and activation of NMDA receptors in LID, but the interaction between LID and CaMKII-modulated NMDA receptor activity is not clear so far.


METHODS
We used 6-hydroxydopamine-lesioned rats to create PD rat model, and at least 21 days of L-DOPA was administrated followed with or without microinjection of CaMKII inhibitor KN-93 into the lesioned striatum of all the PD rats and sham rats. A surface receptor cross-linking assay was used to distinguish expression of striatal NMDA receptors in surface and intracellular compartments.


RESULTS
L-DOPA treatment enhanced surface levels of GluN1 expression and reduced its intracellular expression, but did not change total levels of GluN1 protein in the lesioned striatum. In contrast, l-DOPA decreased GluN2A surface expression but increased its intracellular expression. L-DOPA increased GluN2B expression preferentially in the surface compartment. We also found that L-DOPA increased CaMKII autophosphorylation at T286 in striatal neurons. The inhibition of CaMKII by microinjecting CaMKII inhibitor KN-93 into the lesioned striatum largely reversed the L-DOPA-induced changes in three subunits. In addition, dyskinetic behaviors of animals were observed alleviated after treatment of KN-93.


CONCLUSIONS
Our research indicates that long-term L-DOPA administration activates CaMKII in striatal neurons. Activated CaMKII is involved at least in part in mediating L-DOPA-induced changes of NMDA receptors surface/intracellular expression.
Department of Neurology, Xinhua Hospital affiliated to Shanghai Jiao Tong University Medical School, Shanghai, People's Republic of China.
Jing
J
Gan
Department of Neurology, Xinhua Hospital affiliated to Shanghai Jiao Tong University Medical School, Shanghai, People's Republic of China.
Chen
C
Qi
Department of Neurology, Xinhua Hospital affiliated to Shanghai Jiao Tong University Medical School, Shanghai, People's Republic of China.
Zhenguo
Z
Liu
D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001596:Benzylamines / Q000008:administration & dosage / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D007980:Levodopa / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D017072:Neostriatum / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D000096926:Benzenesulfonamides
D000978:Antiparkinson Agents; D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D007980:Levodopa; D016194:Receptors, N-Methyl-D-Aspartate; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides
GluN1; GluN2A; GluN2B; KN-93; dopamine; glutamate