title: Redistribution of GABAB(1) protein and atypical GABAB responses in GABAB(2)-deficient mice.
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.
authors.affiliation: Pharmazentrum, Department of Clinical-Biological Sciences, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Gassmann
authors.forename: Hamdy
authors.initials: H
authors.lastname: Shaban
authors.forename: Réjan
authors.initials: R
authors.lastname: Vigot
authors.forename: Gilles
authors.initials: G
authors.lastname: Sansig
authors.forename: Corinne
authors.initials: C
authors.lastname: Haller
authors.forename: Samuel
authors.initials: S
authors.lastname: Barbieri
authors.forename: Yann
authors.initials: Y
authors.lastname: Humeau
authors.forename: Valérie
authors.initials: V
authors.lastname: Schuler
authors.forename: Matthias
authors.initials: M
authors.lastname: Müller
authors.forename: Bernd
authors.initials: B
authors.lastname: Kinzel
authors.forename: Klaus
authors.initials: K
authors.lastname: Klebs
authors.forename: Markus
authors.initials: M
authors.lastname: Schmutz
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Froestl
authors.forename: Jakob
authors.initials: J
authors.lastname: Heid
authors.forename: Peter H
authors.initials: PH
authors.lastname: Kelly
authors.forename: Clive
authors.initials: C
authors.lastname: Gentry
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Jaton
authors.forename: Herman
authors.initials: H
authors.lastname: Van der Putten
authors.forename: Cédric
authors.initials: C
authors.lastname: Mombereau
authors.forename: Lucas
authors.initials: L
authors.lastname: Lecourtier
authors.forename: Johannes
authors.initials: J
authors.lastname: Mosbacher
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Fritschy
authors.forename: Andreas
authors.initials: A
authors.lastname: Lüthi
authors.forename: Klemens
authors.initials: K
authors.lastname: Kaupmann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001923:Brain Chemistry; D019281:Dimerization; D004569:Electroencephalography; D018755:GABA Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D006930:Hyperalgesia / Q000235:genetics* / Q000473:pathology; D006948:Hyperkinesis / Q000235:genetics* / Q000473:pathology; D008569:Memory Disorders / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010147:Pain Measurement; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D011869:Radioligand Assay; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism*; D012640:Seizures / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D018755:GABA Agonists; D015221:Potassium Channels; D021122:Protein Subunits; D018080:Receptors, GABA-B