Native GABA(B) receptors are heteromultimers with a family of auxiliary subunits.
GABA(B) receptors are the G-protein-coupled receptors for gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain. They are expressed in almost all neurons of the brain, where they regulate synaptic transmission and signal propagation by controlling the activity of voltage-gated calcium (Ca(v)) and inward-rectifier potassium (K(ir)) channels. Molecular cloning revealed that functional GABA(B) receptors are formed by the heteromeric assembly of GABA(B1) with GABA(B2) subunits. However, cloned GABA(B(1,2)) receptors failed to reproduce the functional diversity observed with native GABA(B) receptors. Here we show by functional proteomics that GABA(B) receptors in the brain are high-molecular-mass complexes of GABA(B1), GABA(B2) and members of a subfamily of the KCTD (potassium channel tetramerization domain-containing) proteins. KCTD proteins 8, 12, 12b and 16 show distinct expression profiles in the brain and associate tightly with the carboxy terminus of GABA(B2) as tetramers. This co-assembly changes the properties of the GABA(B(1,2)) core receptor: the KCTD proteins increase agonist potency and markedly alter the G-protein signalling of the receptors by accelerating onset and promoting desensitization in a KCTD-subtype-specific manner. Taken together, our results establish the KCTD proteins as auxiliary subunits of GABA(B) receptors that determine the pharmacology and kinetics of the receptor response.
Schwenk
Jochen
J
Institute of Physiology II, University of Freiburg, Engesserstrasse 4, 79108 Freiburg, Germany.
Metz
Michaela
M
Zolles
Gerd
G
Turecek
Rostislav
R
Fritzius
Thorsten
T
Bildl
Wolfgang
W
Tarusawa
Etsuko
E
Kulik
Akos
A
Unger
Andreas
A
Ivankova
Klara
K
Seddik
Riad
R
Tiao
Jim Y
JY
Rajalu
Mathieu
M
Trojanova
Johana
J
Rohde
Volker
V
Gassmann
Martin
M
Schulte
Uwe
U
Fakler
Bernd
B
Bettler
Bernhard
B
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004553:Electric Conductivity; D058786:GABA-B Receptor Agonists; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018080:Receptors, GABA-B / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction; D014981:Xenopus
D058786:GABA-B Receptor Agonists; D046912:Multiprotein Complexes; D015221:Potassium Channels; D021122:Protein Subunits; D018080:Receptors, GABA-B; D020962:Heterotrimeric GTP-Binding Proteins; D011188:Potassium
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