Allosteric functioning of dimeric class C G‐protein‐coupled receptors

Whereas most membrane receptors are oligomeric entities, G‐protein‐coupled receptors have long been thought to function as monomers. Within the last 15 years, accumulating data have indicated that G‐protein‐coupled receptors can form dimers or even higher ordered oligomers, but the general functional significance of this phenomena is not yet clear. Among the large G‐protein‐coupled receptor family, class C receptors represent a well‐recognized example of constitutive dimers, both subunits being linked, in most cases, by a disulfide bridge. In this review article, we show that class C G‐protein‐coupled receptors are multidomain proteins and highlight the importance of their dimerization for activation. We illustrate several consequences of this in terms of specific functional properties and drug development.

[1]  F. Gasparini,et al.  The Non-competitive Antagonists 2-Methyl-6-(phenylethynyl)pyridine and 7-Hydroxyiminocyclopropan[b]chromen-1a-carboxylic Acid Ethyl Ester Interact with Overlapping Binding Pockets in the Transmembrane Region of Group I Metabotropic Glutamate Receptors* , 2000, The Journal of Biological Chemistry.

[2]  L. Prézeau,et al.  Closure of the Venus flytrap module of mGlu8 receptor and the activation process: Insights from mutations converting antagonists into agonists , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Xiaodong Li,et al.  Different functional roles of T1R subunits in the heteromeric taste receptors. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Gilles Labesse,et al.  No Ligand Binding in the GB2 Subunit of the GABABReceptor Is Required for Activation and Allosteric Interaction between the Subunits , 2002, The Journal of Neuroscience.

[5]  Yoshihiro Kubo,et al.  Ligand-induced rearrangement of the dimeric metabotropic glutamate receptor 1α , 2004, Nature Structural &Molecular Biology.

[6]  F. Marshall,et al.  GABAB receptors - the first 7TM heterodimers. , 1999, Trends in pharmacological sciences.

[7]  L. Prézeau,et al.  The Heptahelical Domain of GABAB2 Is Activated Directly by CGP7930, a Positive Allosteric Modulator of the GABAB Receptor* , 2004, Journal of Biological Chemistry.

[8]  Qi Wu,et al.  NCD3G: a novel nine-cysteine domain in family 3 GPCRs , 2004 .

[9]  H. Schiöth,et al.  The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. , 2003, Molecular pharmacology.

[10]  L. Prézeau,et al.  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. , 2000, Molecular pharmacology.

[11]  J. Kemp,et al.  Positive allosteric modulators of metabotropic glutamate 1 receptor: Characterization, mechanism of action, and binding site , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Kolakowski Lf.  GCRDB: A G-PROTEIN-COUPLED RECEPTOR DATABASE , 1994 .

[13]  N. Kunishima,et al.  Structural views of the ligand-binding cores of a metabotropic glutamate receptor complexed with an antagonist and both glutamate and Gd3+ , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[14]  L. F. Kolakowski.  GCRDb: a G-protein-coupled receptor database. , 1994, Receptors & channels.

[15]  J. Northup,et al.  Evidence for Distinct Cation and Calcimimetic Compound (NPS 568) Recognition Domains in the Transmembrane Regions of the Human Ca2+ Receptor* , 2002, The Journal of Biological Chemistry.

[16]  K. Ray,et al.  Cys-140 Is Critical for Metabotropic Glutamate Receptor-1 Dimerization* , 2000, The Journal of Biological Chemistry.

[17]  S. Wilt,et al.  Heterodimerization of Calcium Sensing Receptors with Metabotropic Glutamate Receptors in Neurons* , 2001, The Journal of Biological Chemistry.

[18]  A. Spiegel,et al.  Human Ca2+ Receptor Cysteine-rich Domain , 2000, The Journal of Biological Chemistry.

[19]  J. Pin,et al.  Molecular Determinants Involved in the Allosteric Control of Agonist Affinity in the GABAB Receptor by the GABAB2 Subunit* , 2004, Journal of Biological Chemistry.

[20]  M. Martick,et al.  Allosteric Activation of a Spring-Loaded Natriuretic Peptide Receptor Dimer by Hormone , 2001, Science.

[21]  L. Snyder,et al.  The Cysteine-rich Region of T1R3 Determines Responses to Intensely Sweet Proteins* , 2004, Journal of Biological Chemistry.

[22]  S. Nakanishi,et al.  Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor , 2000, Nature.

[23]  S. Mennerick,et al.  Covalent and noncovalent interactions mediate metabotropic glutamate receptor mGlu5 dimerization. , 2001, Molecular pharmacology.

[24]  L. Prézeau,et al.  Ca 2 1 Requirement for High-Affinity g-Aminobutyric Acid ( GABA ) Binding at GABAB Receptors : Involvement of Serine 269 of the GABABR 1 Subunit , 2000 .

[25]  Julie Perroy,et al.  A Single Subunit (GB2) Is Required for G-protein Activation by the Heterodimeric GABAB Receptor* , 2002, The Journal of Biological Chemistry.

[26]  A. Lawrence,et al.  CGP7930: a positive allosteric modulator of the GABAB receptor. , 2007, CNS drug reviews.

[27]  P. Saintot,et al.  Locking the Dimeric GABAB G-Protein-Coupled Receptor in Its Active State , 2004, The Journal of Neuroscience.

[28]  L. Prézeau,et al.  Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors. , 2003, Pharmacology & therapeutics.

[29]  J. Bockaert,et al.  Molecular tinkering of G protein‐coupled receptors: an evolutionary success , 1999, The EMBO journal.

[30]  A. Spiegel,et al.  Identification of the Cysteine Residues in the Amino-terminal Extracellular Domain of the Human Ca2+ Receptor Critical for Dimerization , 1999, The Journal of Biological Chemistry.

[31]  L. Prézeau,et al.  C-Terminal Interaction Is Essential for Surface Trafficking But Not for Heteromeric Assembly of GABAB Receptors , 2001, The Journal of Neuroscience.

[32]  Michel Bouvier,et al.  Oligomerization of G-protein-coupled transmitter receptors , 2001, Nature Reviews Neuroscience.

[33]  Y. Jan,et al.  A Trafficking Checkpoint Controls GABAB Receptor Heterodimerization , 2000, Neuron.

[34]  G. Köhr,et al.  Importance of the gamma-aminobutyric acid(B) receptor C-termini for G-protein coupling. , 2002, Molecular pharmacology.

[35]  L. Prézeau,et al.  Closed state of both binding domains of homodimeric mGlu receptors is required for full activity , 2004, Nature Structural &Molecular Biology.

[36]  L. Prézeau,et al.  Allosteric interactions between GB1 and GB2 subunits are required for optimal GABAB receptor function , 2001, The EMBO journal.

[37]  Jayaram Chandrashekar,et al.  An amino-acid taste receptor , 2002, Nature.

[38]  N. Ryba,et al.  Mammalian Sweet Taste Receptors , 2001, Cell.

[39]  N. Ryba,et al.  The Receptors for Mammalian Sweet and Umami Taste , 2003, Cell.

[40]  S. Nakanishi,et al.  Amino Acid Mutagenesis of the Ligand Binding Site and the Dimer Interface of the Metabotropic Glutamate Receptor 1 , 2003, The Journal of Biological Chemistry.

[41]  S. Nakanishi,et al.  Cryptic dimer interface and domain organization of the extracellular region of metabotropic glutamate receptor subtype 1. , 2000, The Journal of biological chemistry.

[42]  I. Wilson,et al.  Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation. , 1999, Science.

[43]  Francine Acher,et al.  Heptahelical domain of metabotropic glutamate receptor 5 behaves like rhodopsin-like receptors , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[44]  D. A. Brown,et al.  GABAB2 Is Essential for G-Protein Coupling of the GABAB Receptor Heterodimer , 2001, The Journal of Neuroscience.

[45]  C. Romano,et al.  Metabotropic Glutamate Receptor 5 Is a Disulfide-linked Dimer* , 1996, The Journal of Biological Chemistry.

[46]  L. Prézeau,et al.  BAY36-7620: a potent non-competitive mGlu1 receptor antagonist with inverse agonist activity. , 2001, Molecular pharmacology.

[47]  M. Bouvier,et al.  Roles of G‐protein‐coupled receptor dimerization , 2004, EMBO reports.

[48]  H. Jingami,et al.  Negative Cooperativity of Glutamate Binding in the Dimeric Metabotropic Glutamate Receptor Subtype 1* , 2004, Journal of Biological Chemistry.