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J. Biol. Chem., Vol. 279, Issue 32, 33352-33358, August 6, 2004

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Group I Metabotropic Glutamate Receptors Mediate a Dual Role of Glutamate in T Cell Activation^*

Rodrigo Pacheco, Francisco Ciruela, Vicent Casadó, Josefa Mallol, Teresa Gallart¶, Carmen Lluis, and Rafael Franco||

From the Department of Biochemistry and Molecular Biology, University of Barcelona, 08028 Barcelona, Spain and ^¶Division of Immunology, Hospital Clínic i Provincial, Fundació Clínic, University of Barcelona, 08026 Barcelona, Spain

Metabotropic glutamate receptors (mGluR) are present in cells of the nervous system, where they are activated by one of the main neurotransmitters, glutamate. They are also expressed in cells outside the nervous system. We identified and characterized two receptors belonging to group I mGluR, mGlu1R and mGlu5R, in human cell lines of lymphoid origin and in resting and activated lymphocytes from human peripheral blood. Both are highly expressed in the human Jurkat T cell line, whereas mGlu5R is expressed only in the human B cell line SKW6.4. In blood lymphocytes, mGlu5R is expressed constitutively, whereas mGlu1R is expressed only upon activation via the T cell receptor-CD3 complex. Group I receptors in the central nervous system are coupled to phospholipase C, whereas in blood lymphocytes, activation of mGlu5R does not trigger this signaling pathway, but instead activates adenylate cyclase. On the other hand, mGlu5R does not mediate ERK1/2 activation, whereas mGlu1R, which is coupled neither to phospholipase C nor to calcium channels and whose activation does not increase cAMP, activates the mitogen-activated protein kinase cascade. The differential expression of mGluR in resting and activated lymphocytes and the different signaling pathways that are triggered when mGlu1Rs or mGlu5Rs are activated point to a key role of glutamate in the regulation of T cell physiological function. The study of the signaling pathways (cAMP production and ERK1/2 phosphorylation) and the proliferative response obtained in the presence of glutamate analogs suggests that mGlu1R and mGlu5R have distinct functions. mGlu5R mediates the reported inhibition of cell proliferation evoked by glutamate, which is reverted by the activation of inducible mGlu1R. This is a novel non-inhibitory action mechanism for glutamate in lymphocyte activation. mGlu1R and mGlu5R thus mediate opposite glutamate effects in human lymphocytes.

Received for publication, February 17, 2004 , and in revised form, June 3, 2004.

^* This study was supported by European Union Grant QLG3-CT-2001-010566, Ministerio de Ciencia y Tecnología Grant SAF2002-03293 (to R. F.) and Fundació Marató of Catalonian Telethon (Fundació Marató de TV3) Grant 02/021010 (to R. F.). 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.

Holder of a Ramón y Cajal research contract signed with the Ministerio de Ciencia y Tecnología.

^|| To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of Barcelona, Martí Franquès 1, Barcelona E-08028, Spain. Tel.: 34-93402-1208; Fax: 34-93402-1219; E-mail: r.franco{at}bq.ub.es.

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