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Redistribution of GABAB(1) protein and atypical GABAB responses in GABAB(2)-deficient mice

Gassmann, Martin and Shaban, Hamdy and Vigot, Réjan and Sansig, Gilles and Haller, Corinne and Barbieri, Samuel and Humeau, Yann and Schuler, Valérie and Müller, Matthias and Kinzel, Bernd and Klebs, Klaus and Schmutz, Markus and Froestl, Wolfgang and Heid, Jakob and Kelly, Peter H. and Gentry, Clive and Jaton, Anne-Lise and Van der Putten, Herman and Mombereau, Cédric and Lecourtier, Lucas and Mosbacher, Johannes and Cryan, John F. and Fritschy, Jean-Marc and Lüthi, Andreas and Kaupmann, Klemens and Bettler, Bernhard. (2004) Redistribution of GABAB(1) protein and atypical GABAB responses in GABAB(2)-deficient mice. Journal of neuroscience, Vol. 24, H. 27. pp. 6086-6097.

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Official URL: http://edoc.unibas.ch/dok/A5262247

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Abstract

GABAB receptors mediate slow synaptic inhibition in the nervous system. In transfected cells, functional GABAB receptors are usually only observed after coexpression of GABAB(1) and GABAB(2) subunits, which established the concept of heteromerization for G-protein-coupled receptors. In the heteromeric receptor, GABAB(1) is responsible for binding of GABA, whereas GABAB(2) is necessary for surface trafficking and G-protein coupling. Consistent with these in vitro observations, the GABAB(1) subunit is also essential for all GABAB signaling in vivo. Mice lacking the GABAB(1) subunit do not exhibit detectable electrophysiological, biochemical, or behavioral responses to GABAB agonists. However, GABAB(1) exhibits a broader cellular expression pattern than GABAB(2), suggesting that GABAB(1) could be functional in the absence of GABAB(2). We now generated GABAB(2)-deficient mice to analyze whether GABAB(1) has the potential to signal without GABAB(2) in neurons. We show that GABAB(2)-/- mice suffer from spontaneous seizures, hyperalgesia, hyperlocomotor activity, and severe memory impairment, analogous to GABAB(1)-/- mice. This clearly demonstrates that the lack of heteromeric GABAB(1,2) receptors underlies these phenotypes. To our surprise and in contrast to GABAB(1)-/- mice, we still detect atypical electrophysiological GABAB responses in hippocampal slices of GABAB(2)-/- mice. Furthermore, in the absence of GABAB(2), the GABAB(1) protein relocates from distal neuronal sites to the soma and proximal dendrites. Our data suggest that association of GABAB(2) with GABAB(1) is essential for receptor localization in distal processes but is not absolutely necessary for signaling. It is therefore possible that functional GABAB receptors exist in neurons that naturally lack GABAB(2) subunits.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Physiology > Molecular Neurobiology Synaptic Plasticity (Bettler)
UniBasel Contributors:Bettler, Bernhard
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Society for Neuroscience
ISSN:0270-6474
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:22 Mar 2012 14:24
Deposited On:22 Mar 2012 13:37

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