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

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.

Response of striosomal opioid signaling to dopamine depletion in 6-hydroxydopamine-lesioned rat model of Parkinson's disease: a potential compensatory role

“…After centrifugation at 21,500 × g for 10 min, the protein lysates were resuspended in 100 mM NaH 2 PO 4 , pH 6.0, 1 mM EDTA, 1% 2-mercaptoethanol, 0.1% sodium dodecyl sulfate, to 1 μg/μl final protein concentration and was heated at 100°C for 3 min. To deglycosylate the opioid receptors, they were then incubated with Endo-β- N -acetyl-glucosaminidase F1 (Sigma-Aldrich, St. Louis, MO) at a final concentration of 100 milliunits/ml at 37°C for 16 h. The deglycosylated protein samples were subjected to the trans-immunoblots, according to the method that we previously reported (Yamamura et al, 2013). Specific antibodies against MOR (1:10,000; Millipore, St. Louis, MO), DOR (1:1000; Abcam, Cambridge, UK), and KOR (1:1000; Abcam) were used.…”

c-Abl Inhibition Exerts Symptomatic Antiparkinsonian Effects Through a Striatal Postsynaptic Mechanism

“…We previously reported that c-Abl inhibition normalized motor impairments in a mouse model of PD induced by N -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this model, activity of Cdk5 can be inhibited by reducing the phosphorylation of Cdk5 at Tyr15 (Cdk5-Tyr15), leading to a decreased phosphorylation of DARPP-32 at Thr75 (DARPP-32-Thr75) in the striatum ( Yamamura et al, 2013 ; Tanabe et al, 2014 ). The present study highlights striatal postsynaptic mechanisms by which c-Abl inhibitors represent a symptomatic antiparkinsonian agent to alleviate motor symptoms.…”

Activation of Protein Kinases and Phosphatases Coupled to Glutamate Receptors Regulates the Phosphorylation State of DARPP32 at Threonine 75 After Repeated Exposure to Cocaine in the Rat Dorsal Striatum in a Ca2+-Dependent Manner

“…Thus, blockade of ryanodine-sensitive Ca 2+ channels in the ER decreased the elevation of the phosphorylation in this study. A previous study have shown that stimulation of mGluR1/5 upregulates pDARPP32-Thr75 via signaling cascades linked to phospholipase C (PLC)/CDK5 in mice ( Yamamura et al, 2013 ). These findings suggest that activation of the PLC pathway leading to CDK5 rather than IP 3 is more effective to evoke the phosphorylation.…”

“…These findings suggest that activation of the PLC pathway leading to CDK5 rather than IP 3 is more effective to evoke the phosphorylation. In addition to CDK5, PKC can be activated by activation of both NMDA receptors and mGluRs via increases in Ca 2+ influx and PI hydrolysis, respectively ( Liao et al, 2001 ; Liu et al, 2001 ; Oh et al, 2013 ; Yamamura et al, 2013 ). Thus, activation of PKC linked to glutamate receptors drives Ca 2+ mobilization, which is likely necessary for the phosphorylation of DARPP32-Thr75 in response to repeated cocaine exposure.…”