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

• Main Authors: Yukio eYamamura, Ryoma eMorigaki, Jiro eKasahara, Hironori eYokoyama, Akie eTanabe, Shinya eOkita, Hidetaka eKoizumi, Shinji eNagahiro, Ryuji eKaji, Satoshi eGoto
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2013-02-01
• Series: Frontiers in Cellular Neuroscience
• Subjects: Cyclin-Dependent Kinase 5; Dopamine; Phosphorylation; Striatum; Cell signaling
• Online Access: http://journal.frontiersin.org/Journal/10.3389/fncel.2013.00012/full

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 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.