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

Cyclin-dependent kinase 5 (Cdk5) is a multifunctional neuronal protein kina se that is required for neurite outgrowth and cortical lamination and that plays an important role in dopaminergic signaling in the neostriatum throug h phosphorylation of Thr-75 of DARPP-32 (dopamine and cAMP-regulated phosph oprotein, molecular mass 32 kDa). Casein kinase 1 (CK1) has been implicated in a variety of cellular functions such as DNA repair, circadian rhythm, a nd intracellular trafficking. In the neostriatum, CK1 has been found to pho sphorylate Ser-137 of DARPP-32. However, first messengers for the regulatio n of Cdk5 or CK1 have remained unknown. Here we report that both Cdk5 and C K1 are regulated by metabotropic glutamate receptors (mGluRs) in neostriata l neurons. (S)3,5-dihydroxyphenylglycine (DHPG), an agonist for group I mGl uRs, increased Cdk5 and CK1 activities in neostriatal slices, leading to th e 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-sp ecific inhibitor, butyrolactone. In contrast, the effects of DHPG on both T hr-75 and Ser-137 were blocked by CK1-7 and IC261, specific inhibitors of C K1, suggesting that activation of Cdk5 by mGluRs requires CK1 activity. In support of this possibility, the DHPG-induced increase in Cdk5 activity, me asured in extracts of neostriatal slices, was abolished by CK1-7 and IC261. Treatment of acutely dissociated neurons with DHPG enhanced voltage-depend ent Ca2+ currents. This enhancement was eliminated by either butyrolactone or CK1-7 and was absent in DARPP-32 knockout mice. Together these results i ndicate that a CK1-Cdk5-DARPP-32 cascade may be involved in the regulation by mGluR agonists of Ca2+ channels.