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Redistribution of GABA B(1) Protein and Atypical GABA B Responses in GABA B(2) -Deficient Mice

2004; Society for Neuroscience; Volume: 24; Issue: 27 Linguagem: Inglês

10.1523/jneurosci.5635-03.2004

1529-2401

Martin Gassmann, Hamdy Shaban, Réjan Vigot, Gilles Sansig, Corinne Haller, Samuel Barbieri, Yann Humeau, Valérie Schuler, Matthias Müller, Bernd Kinzel, K. Klebs, Markus Schmutz, Wolfgang Froestl, Jakob Heid, Peter H. Kelly, Clive Gentry, Anne-Lise Jaton, Herman van der Putten, Cédric Mombereau, Lucas Lecourtier, Johannes Mosbacher, John F. Cryan, Jean‐Marc Fritschy, Andreas Lüthi, Klemens Kaupmann, Bernhard Bettler,

Lipid Membrane Structure and Behavior

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.