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J. Biol. Chem., Vol. 282, Issue 16, 12143-12153, April 20, 2007

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Actin-binding Protein -Actinin-1 Interacts with the Metabotropic Glutamate Receptor Type 5b and Modulates the Cell Surface Expression and Function of the Receptor^*

Nuria Cabello, Rosaria Remelli¹, Laia Canela, Ana Soriguera, Josefa Mallol, Enric I. Canela, Melanie J. Robbins^¶, Carme Lluis, Rafael Franco, R. A. Jeffrey McIlhinney, and Francisco Ciruela²

From the Institut d'Investigacions Biomèdiques August Pi i Sunyer and Department of Biochemistry and Molecular Biology, University of Barcelona, Facultat de Biologia, Avda. Diagonal 645, Barcelona 08028, Spain, the Medical Research Council Anatomical Neuropharmacology Unit, Oxford OX1 3TH, United Kingdom, and the ^¶Department of Schizophrenia & Bipolar Neurophysiology and Pharmacology, Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, Harlow, Essex CM19 5AW, United Kingdom

Receptors for neurotransmitters require scaffolding proteins for membrane microdomain targeting and for regulating receptor function. Using a yeast two-hybrid screen, -actinin-1, a major F-actin cross-linking protein, was identified as a binding partner for the C-terminal domain of metabotropic glutamate receptor type 5b (mGlu_5b receptor). Co-expression, co-immunoprecipitation, and pull-down experiments showed a close and specific interaction between mGlu_5b receptor and -actinin-1 in both transfected HEK-293 cells and rat striatum. The interaction of -actinin-1 with mGlu_5b receptor modulated the cell surface expression of the receptor. This was dependent on the binding of -actinin-1 to the actin cytoskeleton. In addition, the -actinin-1/mGlu_5b receptor interaction regulated receptor-mediated activation of the mitogen-activated protein kinase pathway. Together, these findings indicate that there is an -actinin-1-dependent mGlu_5b receptor association with the actin cytoskeleton modulating receptor cell surface expression and functioning.

Received for publication, September 15, 2006 , and in revised form, February 7, 2007.

^* This work was supported by the Ministerio de Educación y Ciencia (Grant SAF2006-05481 to R. F., Grant SAF2005-00170 to E. C., and Grant SAF2005-00903 to F. C.). 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.

¹ A Ph.D. student funded by GlaxoSmithKline (UK) and the Biotechnology and Biological Sciences and Research Council.

² Recipient of a Ramón y Cajal research contract signed with the Ministerio de Educación y Ciencia. To whom correspondence should be addressed. Tel.: 34-934-039-280; Fax: 34-934-021-219; E-mail: fciruela{at}ub.edu.

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