TY - JOUR
T1 - Redistribution of GABAB(1) protein and atypical GABAB responses in GABAB(2)-deficient mice
AU - Gassmann, Martin
AU - Shaban, Hamdy
AU - Vigot, Réjan
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
PY - 2004/7/7
Y1 - 2004/7/7
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.
AB - 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.
KW - G-protein
KW - GABA
KW - GPCR
KW - Heterodimerization
KW - Metabotropic
KW - Trafficking
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UR - http://www.scopus.com/inward/citedby.url?scp=3042834635&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.5635-03.2004
DO - 10.1523/JNEUROSCI.5635-03.2004
M3 - Article
C2 - 15240800
AN - SCOPUS:3042834635
VL - 24
SP - 6086
EP - 6097
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 27
ER -