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J. Biol. Chem. 283 (20): 14072-14083

© 2008 by The American Society for Biochemistry and Molecular Biology, Inc.

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

Formula

Vikas Kumar, Yuh-Jiin I. Jong, , and Karen L. O'Malley1

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

Abstract: 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 Gq/11 coupling or introduction of a dominant negative G{alpha}q construct in striatal neurons prevented nuclear Ca2+ changes following receptor activation. These data indicate that nuclear mGlu5 receptors couple to Gq/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 Gq/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. Revision received 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.


Formula

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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