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PMID: 11331581 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Allosteric interactions between GB1 and GB2 subunits are required for optimal GABA(B) receptor function.

The EMBO journal ·Vol. 20 ·No. 9 ·2001-05-01 ·Pages 2152-9

Galvez T, Duthey B, Kniazeff J, Blahos J, Rovelli G, Bettler B, Prézeau L, Pin JP

Abstract

Recent studies on G-protein-coupled receptors revealed that they can dimerize. However, the role of each subunit in the activation process remains unclear. The gamma-amino-n-butyric acid type B (GABA(B)) receptor is comprised of two subunits: GB1 and GB2. Both consist of an extracellular domain (ECD) and a heptahelical domain composed of seven transmembrane alpha-helices, loops and the C-terminus (HD). Whereas GB1 ECD plays a critical role in ligand binding, GB2 is required not only to target GB1 subunit to the cell surface but also for receptor activation. Here, by analysing chimeric GB subunits, we show that only GB2 HD contains the determinants required for G-protein signalling. However, the HD of GB1 improves coupling efficacy. Conversely, although GB1 ECD is sufficient to bind GABA(B) ligands, the ECD of GB2 increases the agonist affinity on GB1, and is necessary for agonist activation of the receptor. These data indicate that multiple allosteric interactions between the two subunits are required for wild-type functioning of the GABA(B) receptor and highlight further the importance of the dimerization process in GPCR activation.

MeSH Terms
Allosteric Regulation/drug effects,physiology Cell Line Dimerization GABA Agonists/pharmacology GABA Antagonists/pharmacology GTP-Binding Proteins/metabolism Gene Expression Humans Kidney/cytology,metabolism Ligands Protein Structure, Tertiary/physiology Protein Subunits Receptors, GABA-B/genetics,metabolism Recombinant Fusion Proteins/drug effects,genetics,metabolism Signal Transduction/drug effects,physiology Structure-Activity Relationship Transfection
Chemicals
GABA Agonists GABA Antagonists Ligands Protein Subunits Receptors, GABA-B Recombinant Fusion Proteins GTP-Binding Proteins
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Galvez T
Mécanismes Moléculaires des Communications Cellulaires, CNRS-UPR9023, CCIPE, 141 Rue de la Cardonille, F-34094 Montpellier, France
Duthey B
Kniazeff J
Blahos J
Rovelli G
Bettler B
Prézeau L
Pin J P
References (37)
37 references, click to expand
  1. The heteromeric GABA-B receptor recognizes G-protein alpha subunit C-termini.
    Neuropharmacology. 1999 Nov;38(11):1657-66 PMID: 10587081
  2. New perspectives for the development of selective metabotropic glutamate receptor ligands.
    Eur J Pharmacol. 1999 Jun 30;375(1-3):277-94 PMID: 10443583
  3. Amino acids in the second and third intracellular loops of the parathyroid Ca2+-sensing receptor mediate efficient coupling to phospholipase C.
    J Biol Chem. 2000 Jun 30;275(26):19955-63 PMID: 10764812
  4. A trafficking checkpoint controls GABA(B) receptor heterodimerization.
    Neuron. 2000 Jul;27(1):97-106 PMID: 10939334
  5. Signal transduction by GABA(B) receptor heterodimers.
    Neuropsychopharmacology. 2000 Oct;23(4 Suppl):S41-9 PMID: 11008066
  6. Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor.
    Nature. 2000 Oct 26;407(6807):971-7 PMID: 11069170
  7. The metabotropic GABAB receptor directly interacts with the activating transcription factor 4.
    J Biol Chem. 2000 Nov 10;275(45):35185-91 PMID: 10924501
  8. The GABAB receptor interacts directly with the related transcription factors CREB2 and ATFx.
    Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13967-72 PMID: 11087824
  9. Mapping the agonist-binding site of GABAB type 1 subunit sheds light on the activation process of GABAB receptors.
    J Biol Chem. 2000 Dec 29;275(52):41166-74 PMID: 10986293
  10. Three-dimensional model of the extracellular domain of the type 4a metabotropic glutamate receptor: new insights into the activation process.
    Protein Sci. 2000 Nov;9(11):2200-9 PMID: 11152130
  11. C-terminal interaction is essential for surface trafficking but not for heteromeric assembly of GABA(b) receptors.
    J Neurosci. 2001 Feb 15;21(4):1189-202 PMID: 11160389
  12. The C-terminal domains of the GABA(b) receptor subunits mediate intracellular trafficking but are not required for receptor signaling.
    J Neurosci. 2001 Feb 15;21(4):1203-10 PMID: 11160390
  13. Functional significance of oligomerization of G-protein-coupled receptors.
    Trends Endocrinol Metab. 2000 Jul;11(5):163-8 PMID: 10856916
  14. A novel site on the Galpha -protein that recognizes heptahelical receptors.
    J Biol Chem. 2001 Feb 2;276(5):3262-9 PMID: 11027680
  15. Atomic structures of periplasmic binding proteins and the high-affinity active transport systems in bacteria.
    Philos Trans R Soc Lond B Biol Sci. 1990 Jan 30;326(1236):341-51; discussion 351-2 PMID: 1970641
  16. Substitution of three amino acids switches receptor specificity of Gq alpha to that of Gi alpha.
    Nature. 1993 May 20;363(6426):274-6 PMID: 8387644
  17. The ligand-binding domain in metabotropic glutamate receptors is related to bacterial periplasmic binding proteins.
    Neuron. 1993 Jul;11(1):41-52 PMID: 8338667
  18. Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.
    Cell. 1993 Dec 31;75(7):1297-303 PMID: 7916660
  19. Domains involved in the specificity of G protein activation in phospholipase C-coupled metabotropic glutamate receptors.
    EMBO J. 1994 Jan 15;13(2):342-8 PMID: 8313879
  20. GCRDb: a G-protein-coupled receptor database.
    Receptors Channels. 1994;2(1):1-7 PMID: 8081729
  21. Phosphinic acid analogues of GABA. 1. New potent and selective GABAB agonists.
    J Med Chem. 1995 Aug 18;38(17):3297-312 PMID: 7650684
  22. The second intracellular loop of metabotropic glutamate receptor 1 cooperates with the other intracellular domains to control coupling to G-proteins.
    J Biol Chem. 1996 Jan 26;271(4):2199-205 PMID: 8567679
  23. Metabotropic glutamate receptor 5 is a disulfide-linked dimer.
    J Biol Chem. 1996 Nov 8;271(45):28612-6 PMID: 8910492
  24. Expression cloning of GABA(B) receptors uncovers similarity to metabotropic glutamate receptors.
    Nature. 1997 Mar 20;386(6622):239-46 PMID: 9069281
  25. How receptors talk to trimeric G proteins.
    Curr Opin Cell Biol. 1997 Apr;9(2):134-42 PMID: 9069253
  26. Role of the second and third intracellular loops of metabotropic glutamate receptors in mediating dual signal transduction activation.
    J Biol Chem. 1998 Mar 6;273(10):5615-24 PMID: 9488690
  27. Intracellular retention of recombinant GABAB receptors.
    J Biol Chem. 1998 Oct 9;273(41):26361-7 PMID: 9756866
  28. GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2.
    Nature. 1998 Dec 17;396(6712):674-9 PMID: 9872315
  29. Heterodimerization is required for the formation of a functional GABA(B) receptor.
    Nature. 1998 Dec 17;396(6712):679-82 PMID: 9872316
  30. GABA(B)-receptor subtypes assemble into functional heteromeric complexes.
    Nature. 1998 Dec 17;396(6712):683-7 PMID: 9872317
  31. Role of heteromer formation in GABAB receptor function.
    Science. 1999 Jan 1;283(5398):74-7 PMID: 9872744
  32. Intermolecular interactions between dimeric calcium-sensing receptor monomers are important for its normal function.
    Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):2834-9 PMID: 10077597
  33. Molecular tinkering of G protein-coupled receptors: an evolutionary success.
    EMBO J. 1999 Apr 1;18(7):1723-9 PMID: 10202136
  34. Mutagenesis and modeling of the GABAB receptor extracellular domain support a venus flytrap mechanism for ligand binding.
    J Biol Chem. 1999 May 7;274(19):13362-9 PMID: 10224098
  35. A simple method to transfer plasmid DNA into neuronal primary cultures: functional expression of the mGlu5 receptor in cerebellar granule cells.
    Neuropharmacology. 1999 Jun;38(6):793-803 PMID: 10465683
  36. The N-terminal domain of gamma-aminobutyric Acid(B) receptors is sufficient to specify agonist and antagonist binding.
    Mol Pharmacol. 1999 Aug;56(2):448-54 PMID: 10419566
  37. Ca(2+) requirement for high-affinity gamma-aminobutyric acid (GABA) binding at GABA(B) receptors: involvement of serine 269 of the GABA(B)R1 subunit.
    Mol Pharmacol. 2000 Mar;57(3):419-26 PMID: 10692480
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/20.9.2152
Published
2001-05-01
Pages
2152-9
Language
English
Region
England
NLM ID
8208664
PMCID
PMC125244
Subset
IM
External Links
PubMed source DOI: 10.1093/emboj/20.9.2152 PMC Full Text View journal details
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