Redistribution of GABAB(1) protein and atypical GABAB responses in GABAB(2)-deficient mice.
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.
Gassmann
Martin
M
Pharmazentrum, Department of Clinical-Biological Sciences, University of Basel, CH-4056 Basel, Switzerland.
Shaban
Hamdy
H
Vigot
Réjan
R
Sansig
Gilles
G
Haller
Corinne
C
Barbieri
Samuel
S
Humeau
Yann
Y
Schuler
Valérie
V
Müller
Matthias
M
Kinzel
Bernd
B
Klebs
Klaus
K
Schmutz
Markus
M
Froestl
Wolfgang
W
Heid
Jakob
J
Kelly
Peter H
PH
Gentry
Clive
C
Jaton
Anne-Lise
AL
Van der Putten
Herman
H
Mombereau
Cédric
C
Lecourtier
Lucas
L
Mosbacher
Johannes
J
Cryan
John F
JF
Fritschy
Jean-Marc
JM
Lüthi
Andreas
A
Kaupmann
Klemens
K
Bettler
Bernhard
B
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
D018755:GABA Agonists; D015221:Potassium Channels; D021122:Protein Subunits; D018080:Receptors, GABA-B