Differential regulation of the Cdk5-dependent phosphorylation sites of inhibitor-1 and DARPP-32 by depolarization |
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Authors: | Nguyen Chan Hosokawa Tomohisa Kuroiwa Mahomi Ip Nancy Y Nishi Akinori Hisanaga Shin-Ichi Bibb James A |
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Institution: | Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Department of Biological Sciences, Tokyo Metropolitan University, Minami-osawa, Hachiohji, Tokyo, Japan; Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka, Japan; Department of Biochemistry, Biotechnology Research Institute and Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China |
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Abstract: | While cyclin-dependent kinase 5 (Cdk5) is of growing importance to neuronal signaling, its regulation remains relatively unexplored. Examination of the mechanism by which NMDA modulates the phosphorylation of protein phosphatase inhibitor-1 at Ser6 and Ser67 and dopamine- and cAMP-regulated phosphoprotein M r 32 000 at Thr75 revealed that generalized depolarization, rather than specific activation of NMDA receptors, was sufficient to induce decreases in these Cdk5 sites. Although no evidence for the involvement of the Cdk5 cofactors p35 or p39, or for L- and T-type voltage-gated Ca2+ channels, was found, evaluation of the role of phosphatases and extracellular cations revealed differential regulation of the three sites. NMDA-induced decreases in the phosphorylation of Thr75 of dopamine- and cAMP-regulated phosphoprotein M r 32 000 required protein phosphatase 1/2A activity and extracellular Ca2+. In contrast, the effects on Ser6 and Ser67 of inhibitor-1 were not cation specific; either Na+ or Ca2+ sufficed. Furthermore, while the decrease in phosphorylation of Ser6 was partially dependent on protein phosphatase 2B, that of Ser67 was independent of the major protein serine/threonine phosphatases, likely indicating the presence of a pathway by which NMDA inhibits Cdk5 activity. Thus, in the striatum the regulation of phosphorylation of Cdk5-dependent sites by NMDA occurs through multiple distinct pathways. |
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Keywords: | cyclin-dependent kinase 5 depolarization dopamine- and cAMP-regulated phosphoprotein N-methyl-d-aspartate protein phosphatase protein phosphatase inhibitor-1 |
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