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Front Cell Neurosci. 2013 Feb 14;7:12. doi: 10.3389/fncel.2013.00012. eCollection 2013.

Dopamine signaling negatively regulates striatal phosphorylation of Cdk5 at tyrosine 15 in mice.

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1
Parkinson's Disease and Dystonia Research Center, Tokushima University Hospital, University of Tokushima Tokushima, Japan ; Department of Neurobiology and Therapeutics, Graduate School of Pharmaceutical Sciences, Institute of Health Bioscience, University of Tokushima Tokushima, Japan.

Abstract

Striatal functions depend on the activity balance between the dopamine and glutamate neurotransmissions. Glutamate inputs activate cyclin-dependent kinase 5 (Cdk5), which inhibits postsynaptic dopamine signaling by phosphorylating DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, 32 kDa) at Thr75 in the striatum. c-Abelson tyrosine kinase (c-Abl) is known to phosphorylate Cdk5 at Tyr15 (Tyr15-Cdk5) and thereby facilitates the Cdk5 activity. We here report that Cdk5 with Tyr15 phosphorylation (Cdk5-pTyr15) is enriched in the mouse striatum, where dopaminergic stimulation inhibited phosphorylation of Tyr15-Cdk5 by acting through the D2 class dopamine receptors. Moreover, in the 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (MPTP) mouse model, dopamine deficiency caused increased phosphorylation of both Tyr15-Cdk5 and Thr75-DARPP-32 in the striatum, which could be attenuated by administration of L-3,4-dihydroxyphenylalanine and imatinib (STI-571), a selective c-Abl inhibitor. Our results suggest a functional link of Cdk5-pTyr15 with postsynaptic dopamine and glutamate signals through the c-Abl kinase activity in the striatum.

KEYWORDS:

cell signaling; cyclin-dependent kinase 5; phosphorylation; striatum

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