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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.

Gan J, Qi C, Liu Z - Drug Des Devel Ther (2015)

Bottom Line: 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.We also found that L-DOPA increased CaMKII autophosphorylation at T286 in striatal neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Xinhua Hospital affiliated to Shanghai Jiao Tong University Medical School, Shanghai, People's Republic of China.

ABSTRACT

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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus

Effects of l-DOPA and KN-93 on α-actinin expressions in the rat striatum.Notes: A representative immunoblot is shown above the quantification. There was no significant change in the lesioned striatum compared to the unlesioned striatum in all groups. Data are expressed in terms of means±SEMs (n=6 per group).Abbreviations:l-DOPA, l-3,4-dihydroxyphenylalanine; KN-93, N-[2-[[[3-(4-chloro-phenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide; U, un-lesioned; L, lesioned; SEM, standard error of the mean.
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f7-dddt-9-2119: Effects of l-DOPA and KN-93 on α-actinin expressions in the rat striatum.Notes: A representative immunoblot is shown above the quantification. There was no significant change in the lesioned striatum compared to the unlesioned striatum in all groups. Data are expressed in terms of means±SEMs (n=6 per group).Abbreviations:l-DOPA, l-3,4-dihydroxyphenylalanine; KN-93, N-[2-[[[3-(4-chloro-phenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide; U, un-lesioned; L, lesioned; SEM, standard error of the mean.

Mentions: In parallel, we monitored the response of an intracellular protein α-actinin to l-DOPA+/KN-93− group and to l-DOPA+/KN-93+ group. No significant change in α-actinin protein levels was observed in the lesioned side relative to the un-lesioned side in all groups (Figure 7).


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.

Gan J, Qi C, Liu Z - Drug Des Devel Ther (2015)

Effects of l-DOPA and KN-93 on α-actinin expressions in the rat striatum.Notes: A representative immunoblot is shown above the quantification. There was no significant change in the lesioned striatum compared to the unlesioned striatum in all groups. Data are expressed in terms of means±SEMs (n=6 per group).Abbreviations:l-DOPA, l-3,4-dihydroxyphenylalanine; KN-93, N-[2-[[[3-(4-chloro-phenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide; U, un-lesioned; L, lesioned; SEM, standard error of the mean.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403745&req=5

f7-dddt-9-2119: Effects of l-DOPA and KN-93 on α-actinin expressions in the rat striatum.Notes: A representative immunoblot is shown above the quantification. There was no significant change in the lesioned striatum compared to the unlesioned striatum in all groups. Data are expressed in terms of means±SEMs (n=6 per group).Abbreviations:l-DOPA, l-3,4-dihydroxyphenylalanine; KN-93, N-[2-[[[3-(4-chloro-phenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide; U, un-lesioned; L, lesioned; SEM, standard error of the mean.
Mentions: In parallel, we monitored the response of an intracellular protein α-actinin to l-DOPA+/KN-93− group and to l-DOPA+/KN-93+ group. No significant change in α-actinin protein levels was observed in the lesioned side relative to the un-lesioned side in all groups (Figure 7).

Bottom Line: 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.We also found that L-DOPA increased CaMKII autophosphorylation at T286 in striatal neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Xinhua Hospital affiliated to Shanghai Jiao Tong University Medical School, Shanghai, People's Republic of China.

ABSTRACT

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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus