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Class C GPCR: Obligatory Heterodimerization of GABAB Receptor

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G-Protein-Coupled Receptor Dimers

Part of the book series: The Receptors ((REC,volume 33))

Abstract

GABAB receptor is the first known G-protein coupled receptor (GPCR) that requires heterodimerization for function. It is comprised of a heterodimeric assembly of GBR1 and GBR2 subunits, each of which consists of an extracellular domain, a seven-helix transmembrane domain, and a cytoplasmic tail. Many regulatory mechanisms exist to limit transmembrane signaling to complete heterodimers. While the extracellular domain of GBR1 is responsible for ligand recognition, the transmembrane domain of GBR2 is required for G-protein activation. In addition, GBR2 facilitates the cell surface expression of GBR1 through coiled-coil interactions in the cytoplasmic region. Lastly, structures of a GBR1:GBR2 ectodomain heterodimer in the resting and active states demonstrate that the ligand-binding subunit GBR1 undergoes domain closure upon agonist binding, while the modulatory subunit GBR2 remains constitutively open. Receptor activation requires the formation of a novel heterodimer interface between membrane proximal domains. In this chapter we review the discovery of GABAB receptor, the critical role of heterodimerization to receptor function, the conformational state of the heterodimer at rest, and the structural mechanism of ligand-dependent receptor activation.

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References

  1. Macdonald RL, Olsen RW. GABAA receptor channels. Annu Rev Neurosci. 1994;17:569–602.

    Article  CAS  PubMed  Google Scholar 

  2. Bettler B, Kaupmann K, Mosbacher J, Gassmann M. Molecular structure and physiological functions of GABA(B) receptors. Physiol Rev. 2004;84(3):835–67.

    Article  CAS  PubMed  Google Scholar 

  3. Bowery NG, Bettler B, Froestl W, Gallagher JP, Marshall F, Raiteri M, et al. International Union of Pharmacology. XXXIII. Mammalian gamma-aminobutyric acid(B) receptors: structure and function. Pharmacol Rev. 2002;54(2):247–64.

    Article  CAS  PubMed  Google Scholar 

  4. Curtis DR, Johnston GA. Amino acid transmitters in the mammalian central nervous system. Ergeb Physiol 1974;69(0):97–188.

    Google Scholar 

  5. Roberts E. Disinhibition as an organizing principle in the nervous system – the role of the GABA system. Application to neurologic and psychiatric disorders. In: Roberts E, Chase TN, Tower DB, editors. GABA in nervous system funciton. New York: Raven Press; 1976. p. 515–39.

    Google Scholar 

  6. Bowery NG, Brown DA. Depolarizing actions of gamma-aminobutyric acid and related compounds on rat superior cervical ganglia in vitro. Br J Pharmacol. 1974;50(2):205–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Adams PR, Brown DA. Actions of gamma-aminobutyric acid on sympathetic ganglion cells. J Physiol. 1975;250(1):85–120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Brown DA, Marsh S. Axonal GABA-receptors in mammalian peripheral nerve trunks. Brain Res. 1978;156(1):187–91.

    Article  CAS  PubMed  Google Scholar 

  9. Bowery NG, Hudson AL. gamma-Aminobutyric acid reduces the evoked release of [3H]-noradrenaline from sympathetic nerve terminals [proceedings]. Br J Pharmacol. 1979;66(1):108P.

    Google Scholar 

  10. Bowery NG, Doble A, Hill DR, Hudson AL, Shaw JS, Turnbull MJ. Baclofen: a selective agonist for a novel type of GABA receptor proceedings. Br J Pharmacol. 1979;67(3):444P–5P.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Bowery NG, Doble A, Hill DR, Hudson AL, Shaw JS, Turnbull MJ, et al. Bicuculline-insensitive GABA receptors on peripheral autonomic nerve terminals. Eur J Pharmacol. 1981;71(1):53–70.

    Article  CAS  PubMed  Google Scholar 

  12. Bowery NG, Hill DR, Hudson AL, Doble A, Middlemiss DN, Shaw J, et al. (−)baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor. Nature. 1980;283(5742):92–4.

    Article  CAS  PubMed  Google Scholar 

  13. Hill DR, Bowery NG. 3H-baclofen and 3H-GABA bind to bicuculline-insensitive GABAB sites in rat brain. Nature. 1981;290(5802):149–52.

    Article  CAS  PubMed  Google Scholar 

  14. Bowery NG, Hudson AL, Price GW. GABAA and GABAB receptor site distribution in the rat central nervous system. Neuroscience. 1987;20(2):365–83.

    Article  CAS  PubMed  Google Scholar 

  15. Chu DC, Albin RL, Young AB, Penney JB. Distribution and kinetics of GABAB binding sites in rat central nervous system: a quantitative autoradiographic study. Neuroscience. 1990;34(2):341–57.

    Article  CAS  PubMed  Google Scholar 

  16. Gassmann M, Bettler B. Regulation of neuronal GABA(B) receptor functions by subunit composition. Nat Rev Neurosci. 2012;13(6):380–94.

    Article  CAS  PubMed  Google Scholar 

  17. Luscher C, Jan LY, Stoffel M, Malenka RC, Nicoll RA. G protein-coupled inwardly rectifying K+ channels (GIRKs) mediate postsynaptic but not presynaptic transmitter actions in hippocampal neurons. Neuron. 1997;19(3):687–95.

    Article  CAS  PubMed  Google Scholar 

  18. Mintz IM, Bean BP. GABAB receptor inhibition of P-type Ca2+ channels in central neurons. Neuron. 1993;10(5):889–98.

    Article  CAS  PubMed  Google Scholar 

  19. Poncer JC, McKinney RA, Gahwiler BH, Thompson SM. Either N- or P-type calcium channels mediate GABA release at distinct hippocampal inhibitory synapses. Neuron. 1997;18(3):463–72.

    Article  CAS  PubMed  Google Scholar 

  20. Slesinger PA, Stoffel M, Jan YN, Jan LY. Defective gamma-aminobutyric acid type B receptor-activated inwardly rectifying K+ currents in cerebellar granule cells isolated from weaver and Girk2 null mutant mice. Proc Natl Acad Sci U S A. 1997;94(22):12210–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Thompson SM, Capogna M, Scanziani M. Presynaptic inhibition in the hippocampus. Trends Neurosci. 1993;16(6):222–7.

    Article  CAS  PubMed  Google Scholar 

  22. Wu LG, Saggau P. Presynaptic inhibition of elicited neurotransmitter release. Trends Neurosci. 1997;20(5):204–12.

    Article  CAS  PubMed  Google Scholar 

  23. Wojcik WJ, Neff NH. Gamma-aminobutyric acid B receptors are negatively coupled to adenylate cyclase in brain, and in the cerebellum these receptors may be associated with granule cells. Mol Pharmacol. 1984;25(1):24–8.

    CAS  PubMed  Google Scholar 

  24. Harrison NL, Lange GD, Barker JL. (-)-Baclofen activates presynaptic GABAB receptors on GABAergic inhibitory neurons from embryonic rat hippocampus. Neurosci Lett. 1988;85(1):105–9.

    Google Scholar 

  25. Kaupmann K, Huggel K, Heid J, Flor PJ, Bischoff S, Mickel SJ, et al. Expression cloning of GABA(B) receptors uncovers similarity to metabotropic glutamate receptors. Nature. 1997;386(6622):239–46.

    Article  CAS  PubMed  Google Scholar 

  26. Hawrot E, Xiao Y, Shi QL, Norman D, Kirkitadze M, Barlow PN. Demonstration of a tandem pair of complement protein modules in GABA(B) receptor 1a. FEBS Lett. 1998;432(3):103–8.

    Article  CAS  PubMed  Google Scholar 

  27. Blein S, Ginham R, Uhrin D, Smith BO, Soares DC, Veltel S, et al. Structural analysis of the complement control protein (CCP) modules of GABA(B) receptor 1a: only one of the two CCP modules is compactly folded. J Biol Chem. 2004;279(46):48292–306.

    Article  CAS  PubMed  Google Scholar 

  28. Billinton A, Upton N, Bowery NG. GABA(B) receptor isoforms GBR1a and GBR1b, appear to be associated with pre- and post-synaptic elements respectively in rat and human cerebellum. Br J Pharmacol. 1999;126(6):1387–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Malitschek B, Ruegg D, Heid J, Kaupmann K, Bittiger H, Frostl W, et al. Developmental changes of agonist affinity at GABABR1 receptor variants in rat brain. Mol Cell Neurosci. 1998;12(1–2):56–64.

    Article  CAS  PubMed  Google Scholar 

  30. Steiger JL, Bandyopadhyay S, Farb DH, Russek SJ. cAMP response element-binding protein, activating transcription factor-4, and upstream stimulatory factor differentially control hippocampal GABABR1a and GABABR1b subunit gene expression through alternative promoters. J Neurosci. 2004;24(27):6115–26.

    Article  CAS  PubMed  Google Scholar 

  31. Biermann B, Ivankova-Susankova K, Bradaia A, Abdel Aziz S, Besseyrias V, Kapfhammer JP, et al. The sushi domains of GABAB receptors function as axonal targeting signals. J Neurosci. 2010;30(4):1385–94.

    Article  CAS  PubMed  Google Scholar 

  32. Jones KA, Borowsky B, Tamm JA, Craig DA, Durkin MM, Dai M, et al. GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2. Nature. 1998;396(6712):674–9.

    Article  CAS  PubMed  Google Scholar 

  33. Kaupmann K, Malitschek B, Schuler V, Heid J, Froestl W, Beck P, et al. GABA(B)-receptor subtypes assemble into functional heteromeric complexes. Nature. 1998;396(6712):683–7.

    Article  CAS  PubMed  Google Scholar 

  34. White JH, Wise A, Main MJ, Green A, Fraser NJ, Disney GH, et al. Heterodimerization is required for the formation of a functional GABA(B) receptor. Nature. 1998;396(6712):679–82.

    Article  CAS  PubMed  Google Scholar 

  35. Kuner R, Kohr G, Grunewald S, Eisenhardt G, Bach A, Kornau HC. Role of heteromer formation in GABAB receptor function. Science. 1999;283(5398):74–7.

    Article  CAS  PubMed  Google Scholar 

  36. Ng GY, Clark J, Coulombe N, Ethier N, Hebert TE, Sullivan R, et al. Identification of a GABAB receptor subunit, gb2, required for functional GABAB receptor activity. J Biol Chem. 1999;274(12):7607–10.

    Article  CAS  PubMed  Google Scholar 

  37. Martin SC, Russek SJ, Farb DH. Molecular identification of the human GABABR2: cell surface expression and coupling to adenylyl cyclase in the absence of GABABR1. Mol Cell Neurosci. 1999;13(3):180–91.

    Article  CAS  PubMed  Google Scholar 

  38. Milligan G. G protein-coupled receptor hetero-dimerization: contribution to pharmacology and function. Br J Pharmacol. 2009;158(1):5–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bartoi T, Rigbolt KT, Du D, Kohr G, Blagoev B, Kornau HC. GABAB receptor constituents revealed by tandem affinity purification from transgenic mice. J Biol Chem. 2010;285(27):20625–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Schwenk J, Metz M, Zolles G, Turecek R, Fritzius T, Bildl W, et al. Native GABA(B) receptors are heteromultimers with a family of auxiliary subunits. Nature. 2010;465(7295):231–5.

    Article  CAS  PubMed  Google Scholar 

  41. Seddik R, Jungblut SP, Silander OK, Rajalu M, Fritzius T, Besseyrias V, et al. Opposite effects of KCTD subunit domains on GABA(B) receptor-mediated desensitization. J Biol Chem. 2012;287(47):39869–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Turecek R, Schwenk J, Fritzius T, Ivankova K, Zolles G, Adelfinger L, et al. Auxiliary GABA receptor subunits uncouple G protein betagamma subunits from effector channels to induce desensitization. Neuron. 2014.

    Google Scholar 

  43. Lagerstrom MC, Schioth HB. Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov. 2008;7(4):339–57.

    Article  PubMed  Google Scholar 

  44. Bayburt TH, Vishnivetskiy SA, McLean MA, Morizumi T, Huang CC, Tesmer JJ, et al. Monomeric rhodopsin is sufficient for normal rhodopsin kinase (GRK1) phosphorylation and arrestin-1 binding. J Biol Chem. 2011;286(2):1420–8.

    Article  CAS  PubMed  Google Scholar 

  45. Chabre M, le Maire M. Monomeric G-protein-coupled receptor as a functional unit. Biochemistry. 2005;44(27):9395–403.

    Article  CAS  PubMed  Google Scholar 

  46. Manglik A, Kobilka B. The role of protein dynamics in GPCR function: insights from the beta2AR and rhodopsin. Curr Opin Cell Biol. 2014;27:136–43.

    Article  CAS  PubMed  Google Scholar 

  47. Pin JP, Kniazeff J, Binet V, Liu J, Maurel D, Galvez T, et al. Activation mechanism of the heterodimeric GABA(B) receptor. Biochem Pharmacol. 2004;68(8):1565–72.

    Article  CAS  PubMed  Google Scholar 

  48. Pin JP, Kniazeff J, Goudet C, Bessis AS, Liu J, Galvez T, et al. The activation mechanism of class-C G-protein coupled receptors. Biol Cell. 2004;96(5):335–42.

    Article  CAS  PubMed  Google Scholar 

  49. Bai M, Trivedi S, Brown EM. Dimerization of the extracellular calcium-sensing receptor (CaR) on the cell surface of CaR-transfected HEK293 cells. J Biol Chem. 1998;273(36):23605–10.

    Article  CAS  PubMed  Google Scholar 

  50. Ward DT, Brown EM, Harris HW. Disulfide bonds in the extracellular calcium-polyvalent cation-sensing receptor correlate with dimer formation and its response to divalent cations in vitro. J Biol Chem. 1998;273(23):14476–83.

    Article  CAS  PubMed  Google Scholar 

  51. Ray K, Hauschild BC, Steinbach PJ, Goldsmith PK, Hauache O, Spiegel AM. Identification of the cysteine residues in the amino-terminal extracellular domain of the human ca(2+) receptor critical for dimerization. Implications for function of monomeric ca(2+) receptor. J Biol Chem. 1999;274(39):27642–50.

    Article  CAS  PubMed  Google Scholar 

  52. Zhang Z, Sun S, Quinn SJ, Brown EM, Bai M. The extracellular calcium-sensing receptor dimerizes through multiple types of intermolecular interactions. J Biol Chem. 2001;276(7):5316–22.

    Article  CAS  PubMed  Google Scholar 

  53. Pidasheva S, Grant M, Canaff L, Ercan O, Kumar U, Hendy GN. Calcium-sensing receptor dimerizes in the endoplasmic reticulum: biochemical and biophysical characterization of CASR mutants retained intracellularly. Hum Mol Genet. 2006;15(14):2200–9.

    Article  CAS  PubMed  Google Scholar 

  54. Romano C, Yang WL, O’Malley KL. Metabotropic glutamate receptor 5 is a disulfide-linked dimer. J Biol Chem. 1996;271(45):28612–6.

    Article  CAS  PubMed  Google Scholar 

  55. Okamoto T, Sekiyama N, Otsu M, Shimada Y, Sato A, Nakanishi S, et al. Expression and purification of the extracellular ligand binding region of metabotropic glutamate receptor subtype 1. J Biol Chem. 1998;273(21):13089–96.

    Article  CAS  PubMed  Google Scholar 

  56. Tsuji Y, Shimada Y, Takeshita T, Kajimura N, Nomura S, Sekiyama N, et al. Cryptic dimer interface and domain organization of the extracellular region of metabotropic glutamate receptor subtype 1. J Biol Chem. 2000;275(36):28144–51.

    CAS  PubMed  Google Scholar 

  57. Nelson G, Hoon MA, Chandrashekar J, Zhang Y, Ryba NJ, Zuker CS. Mammalian sweet taste receptors. Cell. 2001;106(3):381–90.

    Article  CAS  PubMed  Google Scholar 

  58. Nelson G, Chandrashekar J, Hoon MA, Feng L, Zhao G, Ryba NJ, et al. An amino-acid taste receptor. Nature. 2002;416(6877):199–202.

    Article  CAS  PubMed  Google Scholar 

  59. Galvez T, Duthey B, Kniazeff J, Blahos J, Rovelli G, Bettler B, et al. Allosteric interactions between GB1 and GB2 subunits are required for optimal GABA(B) receptor function. EMBO J. 2001;20(9):2152–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Margeta-Mitrovic M, Jan YN, Jan LY. Ligand-induced signal transduction within heterodimeric GABA(B) receptor. Proc Natl Acad Sci U S A. 2001;98(25):14643–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Monnier C, Tu H, Bourrier E, Vol C, Lamarque L, Trinquet E, et al. Trans-activation between 7TM domains: implication in heterodimeric GABA(B) receptor activation. EMBO J. 2011;30(1):32–42.

    Article  CAS  PubMed  Google Scholar 

  62. Malitschek B, Schweizer C, Keir M, Heid J, Froestl W, Mosbacher J, et al. The N-terminal domain of gamma-aminobutyric acid(B) receptors is sufficient to specify agonist and antagonist binding. Mol Pharmacol. 1999;56(2):448–54.

    CAS  PubMed  Google Scholar 

  63. Kniazeff J, Galvez T, Labesse G, Pin JP. No ligand binding in the GB2 subunit of the GABA(B) receptor is required for activation and allosteric interaction between the subunits. J Neurosci. 2002;22(17):7352–61.

    CAS  PubMed  Google Scholar 

  64. Liu J, Maurel D, Etzol S, Brabet I, Ansanay H, Pin JP, et al. Molecular determinants involved in the allosteric control of agonist affinity in the GABAB receptor by the GABAB2 subunit. J Biol Chem. 2004;279(16):15824–30.

    Article  CAS  PubMed  Google Scholar 

  65. Nomura R, Suzuki Y, Kakizuka A, Jingami H. Direct detection of the interaction between recombinant soluble extracellular regions in the heterodimeric metabotropic gamma-aminobutyric acid receptor. J Biol Chem. 2008;283(8):4665–73.

    Article  CAS  PubMed  Google Scholar 

  66. Duthey B, Caudron S, Perroy J, Bettler B, Fagni L, Pin JP, et al. A single subunit (GB2) is required for G-protein activation by the heterodimeric GABA(B) receptor. J Biol Chem. 2002;277(5):3236–41.

    Article  CAS  PubMed  Google Scholar 

  67. Havlickova M, Prezeau L, Duthey B, Bettler B, Pin JP, Blahos J. The intracellular loops of the GB2 subunit are crucial for G-protein coupling of the heteromeric gamma-aminobutyrate B receptor. Mol Pharmacol. 2002;62(2):343–50.

    Article  CAS  PubMed  Google Scholar 

  68. Margeta-Mitrovic M, Jan YN, Jan LY. Function of GB1 and GB2 subunits in G protein coupling of GABA(B) receptors. Proc Natl Acad Sci U S A. 2001;98(25):14649–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Robbins MJ, Calver AR, Filippov AK, Hirst WD, Russell RB, Wood MD, et al. GABA(B2) is essential for g-protein coupling of the GABA(B) receptor heterodimer. J Neurosci. 2001;21(20):8043–52.

    CAS  PubMed  Google Scholar 

  70. Calver AR, Robbins MJ, Cosio C, Rice SQ, Babbs AJ, Hirst WD, et al. The C-terminal domains of the GABA(b) receptor subunits mediate intracellular trafficking but are not required for receptor signaling. J Neurosci. 2001;21(4):1203–10.

    CAS  PubMed  Google Scholar 

  71. Margeta-Mitrovic M, Jan YN, Jan LY. A trafficking checkpoint controls GABA(B) receptor heterodimerization. Neuron. 2000;27(1):97–106.

    Article  CAS  PubMed  Google Scholar 

  72. Pagano A, Rovelli G, Mosbacher J, Lohmann T, Duthey B, Stauffer D, et al. C-terminal interaction is essential for surface trafficking but not for heteromeric assembly of GABA(b) receptors. J Neurosci. 2001;21(4):1189–202.

    CAS  PubMed  Google Scholar 

  73. Geng Y, Xiong D, Mosyak L, Malito DL, Kniazeff J, Chen Y, et al. Structure and functional interaction of the extracellular domain of human GABA(B) receptor GBR2. Nat Neurosci. 2012;15(7):970–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Matsushita S, Nakata H, Kubo Y, Tateyama M. Ligand-induced rearrangements of the GABA(B) receptor revealed by fluorescence resonance energy transfer. J Biol Chem. 2010;285(14):10291–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kammerer RA, Frank S, Schulthess T, Landwehr R, Lustig A, Engel J. Heterodimerization of a functional GABAB receptor is mediated by parallel coiled-coil alpha-helices. Biochemistry. 1999;38(40):13263–9.

    Article  CAS  PubMed  Google Scholar 

  76. Geng Y, Bush M, Mosyak L, Wang F, Fan QR. Structural mechanism of ligand activation in human GABA(B) receptor. Nature. 2013;504(7479):254–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kunishima N, Shimada Y, Tsuji Y, Sato T, Yamamoto M, Kumasaka T, et al. Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature. 2000;407(6807):971–7.

    Article  CAS  PubMed  Google Scholar 

  78. Tsuchiya D, Kunishima N, Kamiya N, Jingami H, Morikawa K. 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 U S A. 2002;99(5):2660–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Muto T, Tsuchiya D, Morikawa K, Jingami H. Structures of the extracellular regions of the group II/III metabotropic glutamate receptors. Proc Natl Acad Sci U S A. 2007;104(10):3759–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. van den Akker F, Zhang X, Miyagi M, Huo X, Misono KS, Yee VC. Structure of the dimerized hormone-binding domain of a guanylyl-cyclase-coupled receptor. Nature. 2000;406(6791):101–4.

    Article  PubMed  Google Scholar 

  81. He X, Chow D, Martick MM, Garcia KC. Allosteric activation of a spring-loaded natriuretic peptide receptor dimer by hormone. Science. 2001;293(5535):1657–62.

    Article  CAS  Google Scholar 

  82. Ogawa H, Qiu Y, Ogata CM, Misono KS. Crystal structure of hormone-bound atrial natriuretic peptide receptor extracellular domain: rotation mechanism for transmembrane signal transduction. J Biol Chem. 2004;279(27):28625–31.

    Article  CAS  PubMed  Google Scholar 

  83. He XL, Dukkipati A, Garcia KC. Structural determinants of natriuretic peptide receptor specificity and degeneracy. J Mol Biol. 2006;361(4):698–714.

    Article  CAS  PubMed  Google Scholar 

  84. Jin R, Singh SK, Gu S, Furukawa H, Sobolevsky AI, Zhou J, et al. Crystal structure and association behaviour of the GluR2 amino-terminal domain. EMBO J. 2009;28(12):1812–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Karakas E, Simorowski N, Furukawa H. Structure of the zinc-bound amino-terminal domain of the NMDA receptor NR2B subunit. EMBO J. 2009;28(24):3910–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kumar J, Schuck P, Jin R, Mayer ML. The N-terminal domain of GluR6-subtype glutamate receptor ion channels. Nat Struct Mol Biol. 2009;16(6):631–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Sack JS, Saper MA, Quiocho FA. Periplasmic binding protein structure and function. Refined X-ray structures of the leucine/isoleucine/valine-binding protein and its complex with leucine. J Mol Biol. 1989;206(1):171–91.

    Article  CAS  PubMed  Google Scholar 

  88. Restituito S, Couve A, Bawagan H, Jourdain S, Pangalos MN, Calver AR, et al. Multiple motifs regulate the trafficking of GABA(B) receptors at distinct checkpoints within the secretory pathway. Mol Cell Neurosci. 2005;28(4):747–56.

    Article  CAS  PubMed  Google Scholar 

  89. Burmakina S, Geng Y, Chen Y, Fan QR. Heterodimeric coiled-coil interactions of human GABAB receptor. Proc Natl Acad Sci U S A. 2014;111(19):6958–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wu H, Wang C, Gregory KJ, Han GW, Cho HP, Xia Y, et al. Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science. 2014;344(6179):58–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Dore AS, Okrasa K, Patel JC, Serrano-Vega M, Bennett K, Cooke RM, et al. Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain. Nature. 2014;511(7511):557–62.

    Article  CAS  PubMed  Google Scholar 

  92. Couve A, Filippov AK, Connolly CN, Bettler B, Brown DA, Moss SJ. Intracellular retention of recombinant GABAB receptors. J Biol Chem. 1998;273(41):26361–7.

    Google Scholar 

  93. Doly S, Shirvani H, Gata G, Meye FJ, Emerit MB, Enslen H, et al. GABAB receptor cell-surface export is controlled by an endoplasmic reticulum gatekeeper. Mol Psychiatry. 2016;21(4):480–90.

    Article  CAS  PubMed  Google Scholar 

  94. Froestl W. Chemistry and pharmacology of GABAB receptor ligands. Adv Pharmacol. 2010;58:19–62.

    Article  CAS  PubMed  Google Scholar 

  95. Cryan JF, Kelly PH, Chaperon F, Gentsch C, Mombereau C, Lingenhoehl K, et al. Behavioral characterization of the novel GABAB receptor-positive modulator GS39783 (N,N’-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): anxiolytic-like activity without side effects associated with baclofen or benzodiazepines. J Pharmacol Exp Ther 2004;310(3):952–63.

    Google Scholar 

  96. Galvez T, Parmentier ML, Joly C, Malitschek B, Kaupmann K, Kuhn R, et al. Mutagenesis and modeling of the GABAB receptor extracellular domain support a venus flytrap mechanism for ligand binding. J Biol Chem. 1999;274(19):13362–9.

    Article  CAS  PubMed  Google Scholar 

  97. Galvez T, Prezeau L, Milioti G, Franek M, Joly C, Froestl W, et al. Mapping the agonist-binding site of GABAB type 1 subunit sheds light on the activation process of GABAB receptors. J Biol Chem. 2000;275(52):41166–74.

    Article  CAS  PubMed  Google Scholar 

  98. Galvez T, Urwyler S, Prezeau L, Mosbacher J, Joly C, Malitschek B, 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. Mol Pharmacol. 2000;57(3):419–26.

    CAS  PubMed  Google Scholar 

  99. Kniazeff J, Saintot PP, Goudet C, Liu J, Charnet A, Guillon G, et al. Locking the dimeric GABA(B) G-protein-coupled receptor in its active state. J Neurosci. 2004;24(2):370–7.

    Article  CAS  PubMed  Google Scholar 

  100. Rondard P, Huang S, Monnier C, Tu H, Blanchard B, Oueslati N, et al. Functioning of the dimeric GABA(B) receptor extracellular domain revealed by glycan wedge scanning. EMBO J. 2008;27(9):1321–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Rosenbaum DM, Zhang C, Lyons JA, Holl R, Aragao D, Arlow DH, et al. Structure and function of an irreversible agonist-beta(2) adrenoceptor complex. Nature. 2011;469(7329):236–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Geng Y, Mosyak L, Kurinov I, Zuo H, Sturchler E, Cheng TC, et al. Structural mechanism of ligand activation in human calcium-sensing receptor. Elife. 2016;5:e13662.

    Google Scholar 

  103. Vafabakhsh R, Levitz J, Isacoff EY. Conformational dynamics of a class C G-protein-coupled receptor. Nature. 2015;524(7566):497–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Huang S, Cao J, Jiang M, Labesse G, Liu J, Pin JP, et al. Interdomain movements in metabotropic glutamate receptor activation. Proc Natl Acad Sci U S A. 2011;108(37):15480–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgement

We thank W.A. Hendrickson for advice and B.H. Cao for help with literature search.

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Authors and Affiliations

  1. Department of Pharmacology, Columbia University, New York, NY, USA

    Qing R. Fan Ph.D. & William Y. Guo

  2. Department of Pathology & Cell Biology, Columbia University, New York, NY, USA

    Qing R. Fan Ph.D.

  3. CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Pudong, Shanghai, China

    Yong Geng

  4. Center for Physics and Biology, The Rockefeller University, New York, NY, USA

    Marisa G. Evelyn

Authors
  1. Qing R. Fan Ph.D.
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  2. William Y. Guo
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  3. Yong Geng
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  4. Marisa G. Evelyn
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Corresponding author

Correspondence to Qing R. Fan Ph.D. .

Editor information

Editors and Affiliations

  1. Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, New York, USA

    Katharine Herrick-Davis

  2. Centre for Translational Pharmacology, Institute of Molecular Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom

    Graeme Milligan

  3. Department of Physiology and Biochemistry, University of Malta, Msida, Malta

    Giuseppe Di Giovanni

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Fan, Q.R., Guo, W.Y., Geng, Y., Evelyn, M.G. (2017). Class C GPCR: Obligatory Heterodimerization of GABAB Receptor. In: Herrick-Davis, K., Milligan, G., Di Giovanni, G. (eds) G-Protein-Coupled Receptor Dimers. The Receptors, vol 33. Humana Press, Cham. https://doi.org/10.1007/978-3-319-60174-8_12

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