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The Journal of Neuroscience, July 7, 2004, 24(27):6086-6097; doi:10.1523/JNEUROSCI.5635-03.2004

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Cellular/Molecular
Redistribution of GABA_B(1) Protein and Atypical GABA_B Responses in GABA_B(2)-Deficient Mice

Martin Gassmann,^1 * Hamdy Shaban,^2,3 * Réjan Vigot,^1 * Gilles Sansig,⁴ Corinne Haller,¹ Samuel Barbieri,¹ Yann Humeau,^2,3,5 Valérie Schuler,⁴ Matthias Müller,⁴ Bernd Kinzel,⁴ Klaus Klebs,⁴ Markus Schmutz,⁴ Wolfgang Froestl,⁴ Jakob Heid,⁴ Peter H. Kelly,⁴ Clive Gentry,⁶ Anne-Lise Jaton,⁴ Herman Van der Putten,⁴ Cédric Mombereau,⁴ Lucas Lecourtier,⁴ Johannes Mosbacher,⁴ John F. Cryan,⁴ Jean-Marc Fritschy,⁷ Andreas Lüthi,^2,3 Klemens Kaupmann,⁴ and Bernhard Bettler¹

¹Pharmazentrum, Department of Clinical-Biological Sciences, University of Basel, CH-4056 Basel, Switzerland, ²Friedrich Miescher Institute, CH-4058 Basel, Switzerland, ³Biozentrum, University of Basel, CH-4056 Basel, Switzerland, ⁴Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland, ⁵Centre National de la Recherche Scientifique, Unité Propre de Recherche 2356, F-67084 Strasbourg, France, ⁶Novartis Institute for Medical Sciences, London WC1E 6B9, United Kingdom, and ⁷Institute of Pharmacology and Toxicology, University of Zürich, CH-8057 Zürich, Switzerland

GABA_B receptors mediate slow synaptic inhibition in the nervous system. In transfected cells, functional GABA_B receptors are usually only observed after coexpression of GABA_B(1) and GABA_B(2) subunits, which established the concept of heteromerization for G-protein-coupled receptors. In the heteromeric receptor, GABA_B(1) is responsible for binding of GABA, whereas GABA_B(2) is necessary for surface trafficking and G-protein coupling. Consistent with these in vitro observations, the GABA_B(1) subunit is also essential for all GABA_B signaling in vivo. Mice lacking the GABA_B(1) subunit do not exhibit detectable electrophysiological, biochemical, or behavioral responses to GABA_B agonists. However, GABA_B(1) exhibits a broader cellular expression pattern than GABA_B(2), suggesting that GABA_B(1) could be functional in the absence of GABA_B(2). We now generated GABA_B(2)-deficient mice to analyze whether GABA_B(1) has the potential to signal without GABA_B(2) in neurons. We show that GABA_B(2)^-/- mice suffer from spontaneous seizures, hyperalgesia, hyperlocomotor activity, and severe memory impairment, analogous to GABA_B(1)^-/- mice. This clearly demonstrates that the lack of heteromeric GABA_B(1,2) receptors underlies these phenotypes. To our surprise and in contrast to GABA_B(1)^-/- mice, we still detect atypical electrophysiological GABA_B responses in hippocampal slices of GABA_B(2)^-/- mice. Furthermore, in the absence of GABA_B(2), the GABA_B(1) protein relocates from distal neuronal sites to the soma and proximal dendrites. Our data suggest that association of GABA_B(2) with GABA_B(1) is essential for receptor localization in distal processes but is not absolutely necessary for signaling. It is therefore possible that functional GABA_B receptors exist in neurons that naturally lack GABA_B(2) subunits.

Key words: GABA; GPCR; G-protein; heterodimerization; metabotropic; trafficking

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Received Oct 31, 2003; revised April 27, 2004; accepted April 27, 2004.

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