Redistribution of GABAB(1)Protein and Atypical GABABResponses in GABAB(2)-Deficient Mice

Medientyp: E-Artikel
Titel: Redistribution of GABAB(1)Protein and Atypical GABABResponses in GABAB(2)-Deficient Mice
Beteiligte: Gassmann, Martin; Shaban, Hamdy; Vigot, Réjan; Sansig, Gilles; Haller, Corinne; Barbieri, Samuel; Humeau, Yann; Schuler, Valérie; Müller, Matthias; Kinzel, Bernd; Klebs, Klaus; Schmutz, Markus; Froestl, Wolfgang; Heid, Jakob; Kelly, Peter H.; Gentry, Clive; Jaton, Anne-Lise; Van der Putten, Herman; Mombereau, Cédric; Lecourtier, Lucas; Mosbacher, Johannes; Cryan, John F.; Fritschy, Jean-Marc; Lüthi, Andreas; [...]
Erschienen: Society for Neuroscience, 2004
Erschienen in: The Journal of Neuroscience
Sprache: Englisch
DOI: 10.1523/jneurosci.5635-03.2004
ISSN: 0270-6474; 1529-2401
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Beschreibung: <jats:p>GABA<jats:sub>B</jats:sub>receptors mediate slow synaptic inhibition in the nervous system. In transfected cells, functional GABA<jats:sub>B</jats:sub>receptors are usually only observed after coexpression of GABA<jats:sub>B(1)</jats:sub>and GABA<jats:sub>B(2)</jats:sub>subunits, which established the concept of heteromerization for G-protein-coupled receptors. In the heteromeric receptor, GABA<jats:sub>B(1)</jats:sub>is responsible for binding of GABA, whereas GABA<jats:sub>B(2)</jats:sub>is necessary for surface trafficking and G-protein coupling. Consistent with these<jats:italic>in vitro</jats:italic>observations, the GABA<jats:sub>B(1)</jats:sub>subunit is also essential for all GABA<jats:sub>B</jats:sub>signaling<jats:italic>in vivo</jats:italic>. Mice lacking the GABA<jats:sub>B(1)</jats:sub>subunit do not exhibit detectable electrophysiological, biochemical, or behavioral responses to GABA<jats:sub>B</jats:sub>agonists. However, GABA<jats:sub>B(1)</jats:sub>exhibits a broader cellular expression pattern than GABA<jats:sub>B(2)</jats:sub>, suggesting that GABA<jats:sub>B(1)</jats:sub>could be functional in the absence of GABA<jats:sub>B(2)</jats:sub>. We now generated GABA<jats:sub>B(2)</jats:sub>-deficient mice to analyze whether GABA<jats:sub>B(1)</jats:sub>has the potential to signal without GABA<jats:sub>B(2)</jats:sub>in neurons. We show that GABA<jats:sub>B(2)</jats:sub><jats:sup>-/-</jats:sup>mice suffer from spontaneous seizures, hyperalgesia, hyperlocomotor activity, and severe memory impairment, analogous to GABA<jats:sub>B(1)</jats:sub><jats:sup>-/-</jats:sup>mice. This clearly demonstrates that the lack of heteromeric GABA<jats:sub>B(1,2)</jats:sub>receptors underlies these phenotypes. To our surprise and in contrast to GABA<jats:sub>B(1)</jats:sub><jats:sup>-/-</jats:sup>mice, we still detect atypical electrophysiological GABA<jats:sub>B</jats:sub>responses in hippocampal slices of GABA<jats:sub>B(2)</jats:sub><jats:sup>-/-</jats:sup>mice. Furthermore, in the absence of GABA<jats:sub>B(2)</jats:sub>, the GABA<jats:sub>B(1)</jats:sub>protein relocates from distal neuronal sites to the soma and proximal dendrites. Our data suggest that association of GABA<jats:sub>B(2)</jats:sub>with GABA<jats:sub>B(1)</jats:sub>is essential for receptor localization in distal processes but is not absolutely necessary for signaling. It is therefore possible that functional GABA<jats:sub>B</jats:sub>receptors exist in neurons that naturally lack GABA<jats:sub>B(2)</jats:sub>subunits.</jats:p>
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