Differential compartmentalization and distinct functions of GABAB receptor variants.
GABAB receptors are the G protein-coupled receptors for the main inhibitory neurotransmitter in the brain, gamma-aminobutyric acid (GABA). Molecular diversity in the GABAB system arises from the GABAB1a and GABAB1b subunit isoforms that solely differ in their ectodomains by a pair of sushi repeats that is unique to GABAB1a. Using a combined genetic, physiological, and morphological approach, we now demonstrate that GABAB1 isoforms localize to distinct synaptic sites and convey separate functions in vivo. At hippocampal CA3-to-CA1 synapses, GABAB1a assembles heteroreceptors inhibiting glutamate release, while predominantly GABAB1b mediates postsynaptic inhibition. Electron microscopy reveals a synaptic distribution of GABAB1 isoforms that agrees with the observed functional differences. Transfected CA3 neurons selectively express GABAB1a in distal axons, suggesting that the sushi repeats, a conserved protein interaction motif, specify heteroreceptor localization. The constitutive absence of GABAB1a but not GABAB1b results in impaired synaptic plasticity and hippocampus-dependent memory, emphasizing molecular differences in synaptic GABAB functions.
Vigot
Réjan
R
Department of Clinical-Biological Sciences, Institute of Physiology, Pharmazentrum, University of Basel, CH-4056 Basel, Switzerland.
Barbieri
Samuel
S
Bräuner-Osborne
Hans
H
Turecek
Rostislav
R
Shigemoto
Ryuichi
R
Zhang
Yan-Ping
YP
Luján
Rafael
R
Jacobson
Laura H
LH
Biermann
Barbara
B
Fritschy
Jean-Marc
JM
Vacher
Claire-Marie
CM
Müller
Matthias
M
Sansig
Gilles
G
Guetg
Nicole
N
Cryan
John F
JF
Kaupmann
Klemens
K
Gassmann
Martin
M
Oertner
Thomas G
TG
Bettler
Bernhard
B
D000818:Animals; D015152:Blotting, Northern; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism* / Q000648:ultrastructure; D007150:Immunohistochemistry; D008568:Memory / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure; D014162:Transfection
D020033:Protein Isoforms; D018080:Receptors, GABA-B