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The Journal of Neuroscience, January 14, 2004, 24(2):370-377; doi:10.1523/JNEUROSCI.3141-03.2004

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Cellular/Molecular
Locking the Dimeric GABA_B G-Protein-Coupled Receptor in Its Active State

Julie Kniazeff,¹ Pierre-Philippe Saintot,¹ Cyril Goudet,¹ Jianfeng Liu,¹ Annie Charnet,² Gilles Guillon,² and Jean-Philippe Pin¹

¹Laboratory for Functional Genomic, Department of Molecular Pharmacology, Centre National de la Recherche Scientifique Unité Propre de Recherche-2580, and ² Institut National de la Santé et de la Recherche Médicale U469, 34094 Montpellier Cedex 5, France

G-protein-coupled receptors (GPCRs) play a major role in cell-cell communication in the CNS. These proteins oscillate between various inactive and active conformations, the latter being stabilized by agonists. Although mutations can lead to constitutive activity, most of these destabilize inactive conformations, and none lock the receptor in an active state. Moreover, GPCRs are known to form dimers, but the role of each protomer in the activation process remains unclear. Here, we show that the heterodimeric GPCR for the main inhibitory neurotransmitter, the GABA_B receptor, can be locked in its active state by introducing two cysteines expected to form a disulphide bridge to maintain the binding domain of the GABA_B1 subunit in a closed form. This constitutively active receptor cannot be inhibited by antagonists, but its normal functioning, activation by agonists, and inhibition by antagonists can be restored after reduction with dithiothreitol. These data show that the closed state of the binding domain of GABA_B1 is sufficient to turn ON this heterodimeric receptor and illustrate for the first time that a GPCR can be locked in an active conformation.

Key words: receptor; baclofen; GABA; metabotropic glutamate receptor; glutamate; activation mechanism

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Received July 1, 2003; revised November 10, 2003; accepted November 10, 2003.

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