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PNAS 98 (20): 11062-11068

Copyright © 2001 by the National Academy of Sciences.

Colloquium Paper


Regulation of cyclin-dependent kinase 5 and casein kinase 1 by metabotropic glutamate receptors

Feng Liu*,{dagger}, Xiao-Hong Ma{ddagger}, Jernej Ule*, James A. Bibb*, Akinori Nishi§, Anthony J. DeMaggio, Zhen Yan{ddagger}, Angus C. Nairn*, and Paul Greengard*

*Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10021; {ddagger}Department of Physiology and Biophysics, State University of New York, School of Medicine and Biomedical Sciences, Buffalo, NY 14214; §Department of Physiology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan; and ICOS Corp., 22021 20th Avenue SE, Bothell, WA 98021

Abstract: Cyclin-dependent kinase 5 (Cdk5) is a multifunctional neuronal protein kinase that is required for neurite outgrowth and cortical lamination and that plays an important role in dopaminergic signaling in the neostriatum through phosphorylation of Thr-75 of DARPP-32 (dopamine and cAMP-regulated phosphoprotein, molecular mass 32 kDa). Casein kinase 1 (CK1) has been implicated in a variety of cellular functions such as DNA repair, circadian rhythm, and intracellular trafficking. In the neostriatum, CK1 has been found to phosphorylate Ser-137 of DARPP-32. However, first messengers for the regulation of Cdk5 or CK1 have remained unknown. Here we report that both Cdk5 and CK1 are regulated by metabotropic glutamate receptors (mGluRs) in neostriatal neurons. (S)-3,5-dihydroxyphenylglycine (DHPG), an agonist for group I mGluRs, increased Cdk5 and CK1 activities in neostriatal slices, leading to the enhanced phosphorylation of Thr-75 and Ser-137 of DARPP-32, respectively. The effect of DHPG on Thr-75, but not on Ser-137, was blocked by a Cdk5-specific inhibitor, butyrolactone. In contrast, the effects of DHPG on both Thr-75 and Ser-137 were blocked by CK1–7 and IC261, specific inhibitors of CK1, suggesting that activation of Cdk5 by mGluRs requires CK1 activity. In support of this possibility, the DHPG-induced increase in Cdk5 activity, measured in extracts of neostriatal slices, was abolished by CK1–7 and IC261. Treatment of acutely dissociated neurons with DHPG enhanced voltage-dependent Ca2+ currents. This enhancement was eliminated by either butyrolactone or CK1–7 and was absent in DARPP-32 knockout mice. Together these results indicate that a CK1-Cdk5-DARPP-32 cascade may be involved in the regulation by mGluR agonists of Ca2+ channels.

{dagger} To whom reprint requests should be addressed. E-mail: liuf{at}

This paper was presented at the Inaugural Arthur M. Sackler Colloquium of the National Academy of Sciences, "Neural Signaling," held February 15–17, 2001, at the National Academy of Sciences in Washington, DC.

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