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 Lecourtier & 6 others Johannes Mosbacher, John F. Cryan, Jean Marc Fritschy, Andreas Lüthi, Klemens Kaupmann, Bernhard Bettler

Research output: Contribution to journalArticle

176 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
Externally publishedYes

Fingerprint

gamma-Aminobutyric Acid
Proteins
Neurons
Hyperalgesia
Carisoprodol
G-Protein-Coupled Receptors
Dendrites
GTP-Binding Proteins
Nervous System
Seizures
Phenotype

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., ... 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

Redistribution of GABAB(1) protein and atypical GABAB responses in GABAB(2)-deficient mice. / 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; Kaupmann, Klemens; Bettler, Bernhard.

In: Journal of Neuroscience, Vol. 24, No. 27, 07.07.2004, p. 6086-6097.

Research output: Contribution to journalArticle

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, PH, Gentry, C, Jaton, AL, Van Der Putten, H, Mombereau, C, Lecourtier, L, Mosbacher, J, Cryan, JF, Fritschy, JM, Lüthi, A, Kaupmann, K & Bettler, B 2004, 'Redistribution of GABAB(1) protein and atypical GABAB responses in GABAB(2)-deficient mice', Journal of Neuroscience, vol. 24, no. 27, pp. 6086-6097. https://doi.org/10.1523/JNEUROSCI.5635-03.2004
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 ; Kaupmann, Klemens ; Bettler, Bernhard. / Redistribution of GABAB(1) protein and atypical GABAB responses in GABAB(2)-deficient mice. In: Journal of Neuroscience. 2004 ; Vol. 24, No. 27. pp. 6086-6097.
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AU - Gassmann, Martin

AU - Shaban, Hamdy

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AU - Sansig, Gilles

AU - Haller, Corinne

AU - Barbieri, Samuel

AU - Humeau, Yann

AU - Schuler, Valérie

AU - Müller, Matthias

AU - Kinzel, Bernd

AU - Klebs, Klaus

AU - Schmutz, Markus

AU - Froestl, Wolfgang

AU - Heid, Jakob

AU - Kelly, Peter H.

AU - Gentry, Clive

AU - Jaton, Anne Lise

AU - Van Der Putten, Herman

AU - Mombereau, Cédric

AU - Lecourtier, Lucas

AU - Mosbacher, Johannes

AU - Cryan, John F.

AU - Fritschy, Jean Marc

AU - Lüthi, Andreas

AU - Kaupmann, Klemens

AU - Bettler, Bernhard

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N2 - 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.

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