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J. Biol. Chem., Vol. 280, Issue 34, 30469-30480, August 26, 2005

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Functional Metabotropic Glutamate Receptors on Nuclei from Brain and Primary Cultured Striatal Neurons

ROLE OF TRANSPORTERS IN DELIVERING LIGAND^*

Yuh-Jiin I. Jong, Vikas Kumar, Ann E. Kingston, Carmelo Romano¶, and Karen L. O'Malley||

From the Departments of Anatomy and Neurobiology and ^¶Ophthalmology, Washington University School of Medicine, St. Louis, Missouri 63110 and Eli Lilly & Co. Ltd., Indianapolis, Indiana 46285-1533

G-protein-coupled receptors are well known for converting an extracellular signal into an intracellular response. Here we showed that the metabotropic glutamate receptor 5 (mGlu5) plays a dynamic intracellular role in signal transduction. Activation of endogenously expressed mGlu5 on striatal nuclear membranes leads to rapid, sustained calcium (Ca²⁺) responses within the nucleoplasm that can be blocked by receptor-specific antagonists. Extracellular ligands such as glutamate and quisqualate reach nuclear receptors via both sodium-dependent transporters and cystine glutamate exchangers. Inhibition of either transport system blocks radiolabeled agonist uptake as well as agonist-induced nuclear Ca²⁺ changes. Impermeable antagonists like LY393053 and LY367366 not only blocked [³H]quisqualate binding but also prevented nontransported agonists such as (RS)-3,5-dihydroxyphenylglycine from inducing intracellular Ca²⁺ changes in heterologous cells. In contrast, neither LY compound prevented quisqualate or glutamate from activating intracellular receptors leading to Ca²⁺ responses. Inasmuch as Ca²⁺ can enter the nucleoplasm via the nuclear pore complex or from the nuclear lumen, the presence of nuclear mGlu5 receptors appeared to amplify the latter process generating a faster nuclear response in heterologous cells. In isolated striatal nuclei, nuclear receptor activation results in the de novo appearance of phosphorylated CREB protein. Thus, activation of nuclear mGlu5 receptors initiates a signaling cascade that is known to alter gene transcription and regulate many paradigms of synaptic plasticity. These studies demonstrated that mGlu5 receptors play a dynamic role in signaling both on and off the plasma membrane.

Received for publication, February 16, 2005 , and in revised form, June 8, 2005.

^* This work was supported by National Institutes of Health Grants MH57817 and MH069646. 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: Dept. of Anatomy and Neurobiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-7087; Fax: 314-362-3446; E-mail: omalleyk{at}pcg.wustl.edu.

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