Review Article | Published:

Organization and functions of mGlu and GABAB receptor complexes

Nature volume 540, pages 6068 (01 December 2016) | Download Citation

Abstract

The neurotransmitters glutamate and γ-aminobutyric acid (GABA) transmit synaptic signals by activating fast-acting ligand-gated ion channels and more slowly acting G-protein-coupled receptors (GPCRs). The GPCRs for these neurotransmitters, metabotropic glutamate (mGlu) and GABAB receptors, are atypical GPCRs with a large extracellular domain and a mandatory dimeric structure. Recent studies have revealed how these receptors are activated through multiple allosteric interactions between subunit domains. It emerges that the molecular complexity of these receptors is further increased through association with trafficking, effector and regulatory proteins. The structure and composition of these receptors present opportunities for therapeutic intervention in mental health and neurological disorders.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & Regulation of neuronal GABAB receptor functions by subunit composition. Nat. Rev. Neurosci. 13, 380–394 (2012)

  2. 2.

    & Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu. Rev. Pharmacol. Toxicol. 50, 295–322 (2010)

  3. 3.

    Chemistry and pharmacology of GABAB receptor ligands. Adv. Pharmacol. 58, 19–62 (2010)

  4. 4.

    & Development of allosteric modulators of GPCRs for treatment of CNS disorders. Neurobiol. Dis. 61, 55–71 (2014)

  5. 5.

    , , , & Structures of mGluRs shed light on the challenges of drug development of allosteric modulators. Curr. Opin. Pharmacol. 20, 1–7 (2015)

  6. 6.

    , , , & Dimers and beyond: the functional puzzles of class C GPCRs. Pharmacol. Ther. 130, 9–25 (2011)

  7. 7.

    , , & GABAB receptors—the first 7TM heterodimers. Trends Pharmacol. Sci. 20, 396–399 (1999)

  8. 8.

    , , & Phospho-dependent accumulation of GABABRs at presynaptic terminals after NMDAR activation. Cell Reports 16, 1962–1973 (2016)

  9. 9.

    et al. A new approach to analyze cell surface protein complexes reveals specific heterodimeric metabotropic glutamate receptors. FASEB J. 25, 66–77 (2011)

  10. 10.

    et al. The oligomeric state sets GABAB receptor signalling efficacy. EMBO J. 30, 2336–2349 (2011).

  11. 11.

    et al. Native GABAB receptors are heteromultimers with a family of auxiliary subunits. Nature 465, 231–235 (2010). Proteomic identification of the KCTD proteins that constitutively associate with the GABAB2 subunit of GABABRs and regulate the kinetics of Gβγ signalling to K+ and Ca2+ effector channels

  12. 12.

    et al. Modular composition and dynamics of native GABAB receptors identified by high-resolution proteomics. Nat. Neurosci. 19, 233–242 (2016). Comprehensive proteomic study reporting the GABABR interactome in the rodent brain, including a functional characterization of the interaction of GABABRs with hyperpolarization-activated cyclic-nucleotide-gated HCN channels.

  13. 13.

    et al. Allosteric interactions between GB1 and GB2 subunits are required for optimal GABAB receptor function. EMBO J. 20, 2152–2159 (2001)

  14. 14.

    et al. Protein complexes are under evolutionary selection to assemble via ordered pathways. Cell 153, 461–470 (2013)

  15. 15.

    et al. GABA receptor cell-surface export is controlled by an endoplasmic reticulum gatekeeper. Mol. Psychiatry 21, 480–490 (2016)

  16. 16.

    , , & Heterodimeric coiled-coil interactions of human GABAB receptor. Proc. Natl Acad. Sci. USA 111, 6958–6963 (2014)

  17. 17.

    et al. Cell-surface protein–protein interaction analysis with time-resolved FRET and snap-tag technologies: application to GPCR oligomerization. Nat. Methods 5, 561–567 (2008)

  18. 18.

    et al. Closed state of both binding domains of homodimeric mGlu receptors is required for full activity. Nat. Struct. Mol. Biol. 11, 706–713 (2004)

  19. 19.

    et al. Segregation of family A G protein-coupled receptor protomers in the plasma membrane. Mol. Pharmacol. 84, 346–352 (2013)

  20. 20.

    et al. Distinct roles of metabotropic glutamate receptor dimerization in agonist activation and G-protein coupling. Proc. Natl Acad. Sci. USA 109, 16342–16347 (2012)

  21. 21.

    et al. Selective actions of novel allosteric modulators reveal functional heteromers of metabotropic glutamate receptors in the CNS. J. Neurosci. 34, 79–94 (2014)

  22. 22.

    et al. Group 1 metabotropic glutamate receptors 1 and 5 form a protein complex in mouse hippocampus and cortex. Proteomics 16, 2698–2705 (2016)

  23. 23.

    . Stability of GABAB receptor oligomers revealed by dual TR-FRET and drug-induced cell surface targeting. FASEB J. 26, 3430–3439 (2012)

  24. 24.

    et al. Single-molecule analysis of fluorescently labeled G-protein-coupled receptors reveals complexes with distinct dynamics and organization. Proc. Natl Acad. Sci. USA 110, 743–748 (2013)

  25. 25.

    , & X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature 462, 745–756 (2009)

  26. 26.

    et al. Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature 407, 971–977 (2000)

  27. 27.

    , , , & Structural views of the ligand-binding cores of a metabotropic glutamate receptor complexed with an antagonist and both glutamate and Gd3+. Proc. Natl Acad. Sci. USA 99, 2660–2665 (2002)

  28. 28.

    , , & Structures of the extracellular regions of the group II/III metabotropic glutamate receptors. Proc. Natl Acad. Sci. USA 104, 3759–3764 (2007)

  29. 29.

    , , , & Structural mechanism of ligand activation in human GABAB receptor. Nature 504, 254–259 (2013). Crystal structures of the heterodimeric extracellular domains of GABAB1 and GABAB2 in the empty, agonist-bound and antagonist-bound forms, reveal that receptor activation involves the formation of a novel interface between subunits

  30. 30.

    et al. Locking the dimeric GABAB G-protein-coupled receptor in its active state. J. Neurosci. 24, 370–377 (2004)

  31. 31.

    et al. Closure of the Venus flytrap module of mGlu8 receptor and the activation process: insights from mutations converting antagonists into agonists. Proc. Natl Acad. Sci. USA 99, 11097–11102 (2002)

  32. 32.

    et al. Structure and functional interaction of the extracellular domain of human GABAB receptor GBR2. Nat. Neurosci. 15, 970–978 (2012)

  33. 33.

    et al. Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain. Nature 511, 557–562 (2014). Together with Wu et al., the first description of a class C 7TMD crystal structure, showing a NAM-binding site located deeper in the structure than the small-ligand-binding site of many class A GPCRs

  34. 34.

    et al. Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science 344, 58–64 (2014).

  35. 35.

    et al. Fragment and structure-based drug discovery for a class C GPCR: discovery of the mGlu5 negative allosteric modulator HTL14242 (3-chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile). J. Med. Chem. 58, 6653–6664 (2015)

  36. 36.

    , , & N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) acts through a novel site as a positive allosteric modulator of group 1 metabotropic glutamate receptors. Mol. Pharmacol. 73, 909–918 (2008)

  37. 37.

    et al. Overlapping binding sites drive allosteric agonism and positive cooperativity in type 4 metabotropic glutamate receptors. FASEB J. 29, 116–130 (2015)

  38. 38.

    et al. Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer. Nature 411, 962–965 (2001)

  39. 39.

    et al. A close structural analog of 2-methyl-6-(phenylethynyl)-pyridine acts as a neutral allosteric site ligand on metabotropic glutamate receptor subtype 5 and blocks the effects of multiple allosteric modulators. Mol. Pharmacol. 68, 1793–1802 (2005)

  40. 40.

    et al. Biased mGlu5-positive allosteric modulators provide in vivo efficacy without potentiating mGlu5 modulation of NMDAR currents. Neuron 86, 1029–1040 (2015). Development of a biased mGlu5 PAM with therapeutic efficacy and an improved side-effect profile

  41. 41.

    et al. Common structural requirements for heptahelical domain function in class A and class C G protein-coupled receptors. J. Biol. Chem. 282, 12154–12163 (2007)

  42. 42.

    et al. Illuminating the activation mechanisms and allosteric properties of metabotropic glutamate receptors. Proc. Natl Acad. Sci. USA 110, E1416–E1425 (2013)

  43. 43.

    et al. Fine tuning of sub-millisecond conformational dynamics controls metabotropic glutamate receptors agonist efficacy. Nat. Commun. 5, 5206 (2014). Single-molecule FRET measurements at the sub-millisecond scale revealed fast dynamics of the mGlu2 VFTD dimer and showed that ligands change the equilibrium between inactive and active states

  44. 44.

    , & Conformational dynamics of a class C G-protein-coupled receptor. Nature 524, 497–501 (2015). Single-molecule FRET study with full-length mGlu2 revealing an intermediate conformational state that is important for the transition between inactive and active states of the receptor

  45. 45.

    et al. Interdomain movements in metabotropic glutamate receptor activation. Proc. Natl Acad. Sci. USA 108, 15480–15485 (2011)

  46. 46.

    , , , & Ligand-induced rearrangement of the dimeric metabotropic glutamate receptor 1α. Nat. Struct. Mol. Biol. 11, 637–642 (2004)

  47. 47.

    et al. Sequential inter- and intrasubunit rearrangements during activation of dimeric metabotropic glutamate receptor 1. Sci. Signal. 5, ra59 (2012)

  48. 48.

    et al. Evidence for a single heptahelical domain being turned on upon activation of a dimeric GPCR. EMBO J. 24, 499–509 (2005)

  49. 49.

    et al. Major ligand-induced rearrangement of the heptahelical domain interface in a GPCR dimer. Nat. Chem. Biol. 11, 134–140 (2015). This study identified distinct dimerization interfaces for the active and inactive forms of the mGlu 7TMD dimer, implying a large movement between the 7TMDs with conformational changes of the dimeric VFTDs

  50. 50.

    , & Asymmetry of GPCR oligomers supports their functional relevance. Trends Pharmacol. Sci. 32, 514–520 (2011)

  51. 51.

    et al. Trans-activation between 7TM domains: implication in heterodimeric GABAB receptor activation. EMBO J. 30, 32–42 (2011)

  52. 52.

    et al. Asymmetric functioning of dimeric metabotropic glutamate receptors disclosed by positive allosteric modulators. J. Biol. Chem. 280, 24380–24385 (2005)

  53. 53.

    et al. A negative allosteric modulator modulates GABAB-receptor signalling through GB2 subunits. Biochem. J. 473, 779–787 (2016)

  54. 54.

    et al. Heptahelical domain of metabotropic glutamate receptor 5 behaves like rhodopsin-like receptors. Proc. Natl Acad. Sci. USA 101, 378–383 (2004)

  55. 55.

    Arrestins come of age: a personal historical perspective. Prog. Mol. Biol. Transl. Sci. 118, 3–18 (2013)

  56. 56.

    , & Molecular mechanisms that desensitize metabotropic glutamate receptor signaling: an overview. Neuropharmacology 66, 24–30 (2013)

  57. 57.

    , , , & Phosphorylation-independent desensitization of GABAB receptor by GRK4. EMBO J. 22, 3816–3824 (2003)

  58. 58.

    et al. The metabotropic glutamate receptor mGluR5 is endocytosed by a clathrin-independent pathway. J. Biol. Chem. 278, 12222–12230 (2003)

  59. 59.

    et al. Phosphorylation and chronic agonist treatment atypically modulate GABAB receptor cell surface stability. J. Biol. Chem. 279, 12565–12573 (2004)

  60. 60.

    & GABAB receptors-associated proteins: potential drug targets in neurological disorders? Curr. Drug Targets 13, 129–144 (2012)

  61. 61.

    & Molecular diversity, trafficking and subcellular localization of GABAB receptors. Pharmacol. Ther. 110, 533–543 (2006)

  62. 62.

    GABAB receptor trafficking and interacting proteins: targets for the development of highly specific therapeutic strategies to treat neurological disorders? Biochem. Pharmacol. 86, 1525–1530 (2013)

  63. 63.

    , , , & GPCR interacting proteins (GIPs) in the nervous system: roles in physiology and pathologies. Annu. Rev. Pharmacol. Toxicol. 50, 89–109 (2010)

  64. 64.

    Metabotropic glutamate receptors and interacting proteins: evolving drug targets. Curr. Drug Targets 13, 145–156 (2012)

  65. 65.

    et al. Auxiliary GABAB receptor subunits uncouple G protein βγ subunits from effector channels to induce desensitization. Neuron 82, 1032–1044 (2014)

  66. 66.

    & Mode of coupling between the β-adrenergic receptor and adenylate cyclase in turkey erythrocytes. Biochemistry 17, 3795 (1978)

  67. 67.

    et al. Pharmacological characterization of GABAB receptor subtypes assembled with auxiliary KCTD subunits. Neuropharmacology 88, 145–154 (2015)

  68. 68.

    et al. GABA blocks pathological but not acute TRPV1 pain signals. Cell 160, 759–770 (2015). Proteomic study reporting that GABAB1 interacts with TRPV1 channels in dorsal root ganglia and reverts the sensitized state of TRPV1 channels independent of G-protein signalling, possibly through allosteric interactions

  69. 69.

    et al. Endoplasmic reticulum sorting and kinesin-1 command the targeting of axonal GABAB receptors. PLoS One 7, e44168 (2012)

  70. 70.

    et al. Cargo of kinesin identified as JIP scaffolding proteins and associated signaling molecules. J. Cell Biol. 152, 959–970 (2001)

  71. 71.

    et al. Calsyntenins mediate TGN exit of APP in a kinesin-1-dependent manner. Traffic 10, 572–589 (2009)

  72. 72.

    et al. Impairment of GABAB receptor dimer by endogenous 14-3-3ζ in chronic pain conditions. EMBO J. 31, 3239–3251 (2012)

  73. 73.

    et al. Rapid antidepressants stimulate the decoupling of GABAB receptors from GIRK/Kir3 channels through increased protein stability of 14-3-3η. Mol. Psychiatry 20, 298–310 (2015)

  74. 74.

    et al. Metabotropic glutamate type 5, dopamine D2 and adenosine A2a receptors form higher-order oligomers in living cells. J. Neurochem. 109, 1497–1507 (2009)

  75. 75.

    et al. Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs. Cell 147, 1011–1023 (2011)

  76. 76.

    et al. Ligands that interact with putative MOR–mGluR5 heteromer in mice with inflammatory pain produce potent antinociception. Proc. Natl Acad. Sci. USA 110, 11595–11599 (2013)

  77. 77.

    et al. A critical role of striatal A2A R–mGlu5 R interactions in modulating the psychomotor and drug-seeking effects of methamphetamine. Addict. Biol. 21, 811–825 (2016)

  78. 78.

    et al. Functional role of striatal A2A, D2, and mGlu5 receptor interactions in regulating striatopallidal GABA neuronal transmission. J. Neurochem. 138, 254–264 (2016)

  79. 79.

    The effective application of biased signaling to new drug discovery. Mol. Pharmacol. 88, 1055–1061 (2015)

  80. 80.

    et al. Homeostatic scaling requires group I mGluR activation mediated by Homer1a. Neuron 68, 1128–1142 (2010)

  81. 81.

    et al. Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome. Nat. Neurosci. 15, 431–440 (2012)

  82. 82.

    , & Novel allosteric modulators of G protein-coupled receptors. J. Biol. Chem. 290, 19478–19488 (2015)

  83. 83.

    & Cellular, synaptic, and circuit effects of antibodies in autoimmune CNS synaptopathies. Handb. Clin. Neurol. 133, 77–93 (2016)

  84. 84.

    et al. A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage. Proc. Natl Acad. Sci. USA 109, 3317–3322 (2012)

  85. 85.

    et al. The sushi domains of secreted GABAB1 isoforms selectively impair GABAB heteroreceptor function. J. Biol. Chem. 283, 31005–31011 (2008)

  86. 86.

    , , & Visualizing protein partnerships in living cells and organisms. Curr. Opin. Chem. Biol. 15, 781–788 (2011)

  87. 87.

    et al. The sushi domains of GABAB receptors function as axonal targeting signals. J. Neurosci. 30, 1385–1394 (2010)

  88. 88.

    et al. NMDA receptor-dependent GABAB receptor internalization via CaMKII phosphorylation of serine 867 in GABAB1. Proc. Natl Acad. Sci. USA 107, 13924–13929 (2010)

  89. 89.

    et al. GISP: a novel brain-specific protein that promotes surface expression and function of GABAB receptors. J. Neurochem. 100, 1003–1017 (2007)

  90. 90.

    et al. GABAB receptor deficiency causes failure of neuronal homeostasis in hippocampal networks. Proc. Natl Acad. Sci. USA 112, E3291–E3299 (2015)

  91. 91.

    et al. GINIP, a Gαi-interacting protein, functions as a key modulator of peripheral GABAB receptor-mediated analgesia. Neuron 84, 123–136 (2014)

  92. 92.

    et al. Gβ5 recruits R7 RGS proteins to GIRK channels to regulate the timing of neuronal inhibitory signaling. Nat. Neurosci. 13, 661–663 (2010)

  93. 93.

    et al. Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors. Neuron 21, 717–726 (1998)

  94. 94.

    , & Differential binding of calmodulin to group I metabotropic glutamate receptors regulates receptor trafficking and signaling. J. Neurosci. 31, 5921–5930 (2011)

  95. 95.

    et al. Preso1 dynamically regulates group I metabotropic glutamate receptors. Nat. Neurosci. 15, 836–844 (2012)

  96. 96.

    et al. PKC phosphorylation regulates mGluR5 trafficking by enhancing binding of Siah-1A. J. Neurosci. 32, 16391–16401 (2012)

  97. 97.

    et al. Tamalin, a PDZ domain-containing protein, links a protein complex formation of group 1 metabotropic glutamate receptors and the guanine nucleotide exchange factor cytohesins. J. Neurosci. 22, 1280–1289 (2002)

  98. 98.

    et al. Activation of the TRPC1 cation channel by metabotropic glutamate receptor mGluR1. Nature 426, 285–291 (2003)

  99. 99.

    et al. Metabotropic glutamate receptor 8-expressing nerve terminals target subsets of GABAergic neurons in the hippocampus. J. Neurosci. 25, 10520–10536 (2005)

  100. 100.

Download references

Acknowledgements

We thank M. Gassmann, J. Kniazeff and X. Rovira for discussions and help with the figures. This work was supported by grants of the Swiss Science Foundation (3100A0-117816) the National Center for Competences in Research (NCCR) ‘Synapsy, Synaptic Basis of Mental Health Disease’ to B.B., and by grants from the Agence National de la Recherche (ANR-12-BSV2-0015; ANR-13-RPIB-0009), the Fondation Recherche Médicale (FRM DEQ20130326522), the Fondation Bettencourt Schueller, and the Fond Unique Interministériel of the French government (FUI, Cell2Lead project) to J.-P.P.

Author information

Affiliations

  1. Centre National de la Recherche Scientifique UMR 5203, Institut de Génomique Fonctionnelle, Université de Montpellier, F-34094 Montpellier, France

    • Jean-Philippe Pin
  2. INSERM, U1191, F-34094 Montpellier, France

    • Jean-Philippe Pin
  3. Department of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland

    • Bernhard Bettler

Authors

  1. Search for Jean-Philippe Pin in:

  2. Search for Bernhard Bettler in:

Contributions

J.-P.P. and B.B. wrote the manuscript together.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jean-Philippe Pin or Bernhard Bettler.

Reviewer Information Nature thanks K. Gregory, F. Marshall and the other anonymous reviewer(s) for their contribution to the peer review of this work.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature20566

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.