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J. Biol. Chem., Vol. 280, Issue 27, 25409-25415, July 8, 2005

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Protein Kinase C Phosphorylation of the Metabotropic Glutamate Receptor mGluR5 on Serine 839 Regulates Ca²⁺ Oscillations^*

Chul Hoon Kim, Stephanie Braud, John T. R. Isaac, and Katherine W. Roche¶

From the NINDS, National Institutes of Health, Bethesda, Maryland 20892 and Medical Research Council Centre for Synaptic Plasticity, Department of Anatomy, University of Bristol, Bristol BS8 1TD, United Kingdom

The activation of Group 1 metabotropic glutamate receptors, mGluR5 and mGluR1, triggers intracellular calcium release; however, mGluR5 activation is unique in that it elicits Ca²⁺ oscillations. A short region of the mGluR5 C terminus is the critical determinant and differs from the analogous region of mGluR1 by a single amino acid residue, Thr-840, which is an aspartic acid (Asp-854) in mGluR1. Previous studies show that mGluR5-elicited Ca²⁺ oscillations require protein kinase C (PKC)-dependent phosphorylation and identify Thr-840 as the phosphorylation site. However, direct phosphorylation of mGluR5 has not been studied in detail. We have used biochemical analyses to directly investigate the phosphorylation of the mGluR5 C terminus. We showed that Ser-839 on mGluR5 is directly phosphorylated by PKC, whereas Thr-840 plays a permissive role. Although Ser-839 is conserved in mGluR1 (Ser-853), it is not phosphorylated, as the adjacent residue (Asp-854) is not permissive; however, mutagenesis of Asp-854 to a permissive alanine residue allows phosphorylation of Ser-853 on mGluR1. We investigated the physiological consequences of mGluR5 Ser-839 phosphorylation using Ca²⁺ imaging. Mutations that eliminate Ser-839 phosphorylation prevent the characteristic mGluR5-dependent Ca²⁺ oscillations. However, mutation of Thr-840 to alanine, which prevents potential Thr-840 phosphorylation but is still permissive for Ser-839 phosphorylation, has no effect on Ca²⁺ oscillations. Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca²⁺ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.

Received for publication, March 10, 2005 , and in revised form, May 6, 2005.

^* This work was supported by the NINDS, National Institutes of Health Intramural Research Program and the Wellcome Trust (to J. T. R. I.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: NINDS, National Institutes of Health, Bldg. 35, Rm. 2C903, Bethesda, MD 20892. Tel.: 301-496-3800; Fax: 301-480-4186; E-mail: rochek{at}ninds.nih.gov.

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