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J. Biol. Chem. 277 (5): 3236-3241

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

A Single Subunit (GB2) Is Required for G-protein Activation by the Heterodimeric GABAB Receptor*

Béatrice DutheyDagger , Sara CaudronDagger , Julie PerroyDagger , Bernhard Bettler§, Laurent FagniDagger , Jean-Philippe PinDagger , and Laurent PrézeauDagger

From the Dagger  CNRS, UPR 9023, Centre CNRS-INSERM de Pharmacologie-Endocrinologie, 34094 Montpellier, France and the § Physiologisches Institut, Pharmazentrum Klingelbergstrasse 50, 4056 Basel, Switzerland

Although G-protein-coupled receptors (GPCRs) have been shown to assemble into functional homo or heteromers, the role of each protomer in G-protein activation is not known. Among the GPCRs, the gamma -aminobutyric acid (GABA) type B receptor (GABABR) is the only one known so far that needs two subunits, GB1 and GB2, to function. The GB1 subunit contains the GABA binding site but is unable to activate G-proteins alone. In contrast the GB2 subunit, which does not bind GABA, has an heptahelical domain able to activate G-proteins when assembled into homodimers (Galvez, T., Duthey, B., Kniazeff, J., Blahos, J., Rovelli, G., Bettler, B., Prézeau, L., and Pin, J.-P. (2001) EMBO J. 20, 2152-2159). In the present study, we have examined the role of each subunit within the GB1-GB2 heteromer, in G-protein coupling. To that end, point mutations in the highly conserved third intracellular loop known to prevent G-protein activation of the related Ca-sensing or metabotropic glutamate receptors were introduced into GB1 and GB2. One mutation, L686P introduced in GB2 prevents the formation of a functional receptor, even though the heteromer reaches the cell surface, and even though the mutated subunit still associates with GB1 and increases GABA affinity on GB1. This was observed either in HEK293 cells where the activation of the G-protein was assessed by measurement of inositol phosphate accumulation, or in cultured neurons where the inhibition of the Ca2+ channel current was measured. In contrast, the same mutation when introduced into GB1 does not modify the G-protein coupling properties of the heteromeric GABAB receptor either in HEK293 cells or in neurons. Accordingly, whereas in all GPCRs the same protein is responsible for both agonist binding and G-protein activation, these two functions are assumed by two distinct subunits in the GABAB heteromer: one subunit, GB1, binds the agonists whereas the other, GB2, activates the G-protein. This illustrates the importance of a single subunit for G-protein activation within a dimeric receptor.

* This work was supported by grants from CNRS, Novartis Pharma (Basel; Switzerland), the program Physique-Chimie du Vivant (PCV), and the Action "Molécules et Cibles Thérapeutique" (AMCT).The costs of publication of this article were defrayed in part by the payment of page charges. The 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: CNRS, UPR 9023, CCIPE, 141 Rue de la Cardonille, 34000 Montpellier, France. Tel.: 33- 467-14-2933; Fax: 33-467-542-432, E-mail:

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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