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

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

Research output: Contribution to journalArticle

178 Citations (Scopus)

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 GABA B(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 GABA B(1)-/- mice, we still detect atypical electrophysiological GABAB responses in hippocampal slices of GABAB(2)-/- mice. Furthermore, in the absence of GABA B(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.

Original languageEnglish
Pages (from-to)6086-6097
Number of pages12
JournalJournal of Neuroscience
Volume24
Issue number27
DOIs
Publication statusPublished - Jul 7 2004

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Keywords

  • G-protein
  • GABA
  • GPCR
  • Heterodimerization
  • Metabotropic
  • Trafficking

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Gassmann, M., Shaban, H., Vigot, R., Sansig, G., Haller, C., Barbieri, S., Humeau, Y., Schuler, V., Müller, M., Kinzel, B., Klebs, K., Schmutz, M., Froestl, W., Heid, J., Kelly, P. H., Gentry, C., Jaton, A. L., Van Der Putten, H., Mombereau, C., ... Bettler, B. (2004). Redistribution of GABAB(1) protein and atypical GABAB responses in GABAB(2)-deficient mice. Journal of Neuroscience, 24(27), 6086-6097. https://doi.org/10.1523/JNEUROSCI.5635-03.2004