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J. Biol. Chem., Vol. 283, Issue 20, 14072-14083, May 16, 2008

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Activated Nuclear Metabotropic Glutamate Receptor mGlu5 Couples to Nuclear G_q/11 Proteins to Generate Inositol 1,4,5-Trisphosphate-mediated Nuclear Ca²⁺ Release^*

From the Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110

Recently we have shown that the metabotropic glutamate 5 (mGlu5) receptor can be expressed on nuclear membranes of heterologous cells or endogenously on striatal neurons where it can mediate nuclear Ca²⁺ changes. Here, pharmacological, optical, and genetic techniques were used to show that upon activation, nuclear mGlu5 receptors generate nuclear inositol 1,4,5-trisphosphate (IP₃) in situ. Specifically, expression of an mGlu5 F767S mutant in HEK293 cells that blocks G_q/11 coupling or introduction of a dominant negative G_q construct in striatal neurons prevented nuclear Ca²⁺ changes following receptor activation. These data indicate that nuclear mGlu5 receptors couple to G_q/11 to mobilize nuclear Ca²⁺. Nuclear mGlu5-mediated Ca²⁺ responses could also be blocked by the phospholipase C (PLC) inhibitor, U73122 [GenBank] , the phosphatidylinositol (PI) PLC inhibitor 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphorylcholine (ET-18-OCH₃), or by using small interfering RNA targeted against PLCβ1 demonstrating that PI-PLC is involved. Direct assessment of inositol phosphate production using a PIP2/IP₃ "biosensor" revealed for the first time that IP₃ can be generated in the nucleus following activation of nuclear mGlu5 receptors. Finally, both IP₃ and ryanodine receptor blockers prevented nuclear mGlu5-mediated increases in intranuclear Ca²⁺. Collectively, this study shows that like plasma membrane receptors, activated nuclear mGlu5 receptors couple to G_q/11 and PLC to generate IP₃-mediated release of Ca²⁺ from Ca²⁺-release channels in the nucleus. Thus the nucleus can function as an autonomous organelle independent of signals originating in the cytoplasm, and nuclear mGlu5 receptors play a dynamic role in mobilizing Ca²⁺ in a specific, localized fashion.

Received for publication, October 15, 2007 , and in revised form, February 7, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants MH57817 and MH69646 (to K. O. M.) and National Institutes of Health Neuroscience Blueprint Core Grant NS057105 to Washington University. This work was also supported by the Bakewell Family Foundation. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

¹ To whom correspondence should be addressed: 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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