Metabotropic glutamate receptors

Overview

Metabotropic glutamate (mGlu) receptors are a family of G protein-coupled receptors activated by the neurotransmitter glutamate [1]. The mGlu family is composed of eight members (named mGlu1 to mGlu₈) which... [read more] are divided in three groups based on similarities of agonist pharmacology, primary sequence and G protein coupling to effector: Group-I (mGlu₁ and mGlu₅), Group-II (mGlu₂ and mGlu₃) and Group-III (mGlu₄, mGlu₆, mGlu₇ and mGlu₈) (see Further reading).

Structurally, mGlu are composed of three juxtaposed domains: a core G protein-activating seven-transmembrane domain (TM), common to all GPCRs, is linked via a rigid cysteine-rich domain (CRD) to the Venus Flytrap domain (VFTD), a large bi-lobed extracellular domain where glutamate binds. mGlu form constitutive dimers, cross-linked by a disulfide bridge. The structures of the VFTD of mGlu₁, mGlu₂, mGlu₃, mGlu₅ and mGlu₇ have been solved [2,3,4,5]. The structure of the 7 transmembrane (TM) domains of both mGlu1 and mGlu5 have been solved, and confirm a general helical organization similar to that of other GPCRs, although the helices appear more compacted [6,7,8]. Recent advances in cryo-electron microscopy have provided structures of full-length mGlu receptor dimers [9]. Studies have revealed the possible formation of heterodimers between either group-I receptors, or within and between group-II and -III receptors [10]. First well characterized in transfected cells, co-localization and specific pharmacological properties also suggest the existence of such heterodimers in the brain [11].[12,13,14]. Beyond heteromerization with other mGlu receptor subtypes, increasing evidence suggests mGlu receptors form heteromers and larger order complexes with class A GPCRs (reviewed in [1]).

The endogenous ligands of mGlu are L-glutamic acid, L-serine-O-phosphate, N-acetylaspartylglutamate (NAAG) and L-cysteine sulphinic acid. Group-I mGlu receptors may be activated by 3,5-DHPG and (S)-3HPG [15] and antagonized by (S)-hexylhomoibotenic acid [16]. Group-II mGlu receptors may be activated by LY389795 [17], LY379268 [17], eglumegad [18,19], DCG-IV and (2R,3R)-APDC [20], and antagonised by eGlu [21] and LY307452 [22,23]. Group-III mGlu receptors may be activated by L-AP4 and (R,S)-4-PPG [24]. An example of an antagonist selective for mGlu receptors is LY341495, which blocks mGlu₂ and mGlu₃ at low nanomolar concentrations, mGlu₈ at high nanomolar concentrations, and mGlu₄, mGlu₅, and mGlu₇ in the micromolar range [25]. In addition to orthosteric ligands that directly interact with the glutamate recognition site, allosteric modulators that bind within the TM domain have been described. Negative allosteric modulators are listed separately. The positive allosteric modulators most often act as ‘potentiators’ of an orthosteric agonist response, without significantly activating the receptor in the absence of agonist.

References

1. Gregory KJ, Goudet C. International Union of Basic and Clinical Pharmacology. CXI. Pharmacology, Signaling, and Physiology of Metabotropic Glutamate Receptors. Pharmacol Rev 2021;73:521-569.
2. Kunishima N, Shimada Y, Tsuji Y, et al. Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature 2000;407:971-7.
3. Muto T, Tsuchiya D, Morikawa K, et al. Structures of the extracellular regions of the group II/III metabotropic glutamate receptors. Proc Natl Acad Sci USA 2007;104:3759-64.
4. Monn JA, Prieto L, Taboada L, et al. Synthesis and pharmacological characterization of C4-disubstituted analogs of 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate: identification of a potent, selective metabotropic glutamate receptor agonist and determination of agonist-bound human mGlu2 and mGlu3 amino terminal domain structures. J Med Chem 2015;58:1776-94.
5. Tsuchiya D, Kunishima N, Kamiya N, et al. 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 2002;99:2660-5.
6. Doré AS, Okrasa K, Patel JC, et al. Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain. Nature 2014;511:557-62.
7. Wu H, Wang C, Gregory KJ, et al. Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science 2014;344:58-64.
8. Christopher JA, Orgován Z, Congreve M, et al. Structure-Based Optimization Strategies for G Protein-Coupled Receptor (GPCR) Allosteric Modulators: A Case Study from Analyses of New Metabotropic Glutamate Receptor 5 (mGlu₅) X-ray Structures. J Med Chem 2019;62:207-222.
9. Koehl A, Hu H, Feng D, et al. Structural insights into the activation of metabotropic glutamate receptors. Nature 2019;566:79-84.
10. Doumazane E, Scholler P, Zwier JM, et al. A new approach to analyze cell surface protein complexes reveals specific heterodimeric metabotropic glutamate receptors. FASEB J 2011;25:66-77.
11. Moreno Delgado D, Møller TC, Ster J, et al. Pharmacological evidence for a metabotropic glutamate receptor heterodimer in neuronal cells. Elife 2017;6:.
12. Yin S, Noetzel MJ, Johnson KA, et al. Selective actions of novel allosteric modulators reveal functional heteromers of metabotropic glutamate receptors in the CNS. J Neurosci 2014;34:79-94.
13. Habrian CH, Levitz J, Vyklicky V, et al. Conformational pathway provides unique sensitivity to a synaptic mGluR. Nat Commun 2019;10:5572.
14. Niswender CM, Jones CK, Lin X, et al. Development and Antiparkinsonian Activity of VU0418506, a Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor 4 Homomers without Activity at mGlu2/4 Heteromers. ACS Chem Neurosci 2016;7:1201-11.
15. Brabet I, Mary S, Bockaert J, et al. Phenylglycine derivatives discriminate between mGluR1- and mGluR5-mediated responses. Neuropharmacology 1995;34:895-903.
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17. Monn JA, Valli MJ, Massey SM, et al. Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors. J Med Chem 1999;42:1027-40.
18. Schoepp DD, Johnson BG, Wright RA, et al. LY354740 is a potent and highly selective group II metabotropic glutamate receptor agonist in cells expressing human glutamate receptors. Neuropharmacology 1997;36:1-11.
19. Wu S, Wright RA, Rockey PK, et al. Group III human metabotropic glutamate receptors 4, 7 and 8: molecular cloning, functional expression, and comparison of pharmacological properties in RGT cells. Brain Res Mol Brain Res 1998;53:88-97.
20. Schoepp DD, Salhoff CR, Wright RA, et al. The novel metabotropic glutamate receptor agonist 2R,4R-APDC potentiates stimulation of phosphoinositide hydrolysis in the rat hippocampus by 3,5-dihydroxyphenylglycine: evidence for a synergistic interaction between group 1 and group 2 receptors. Neuropharmacology 1996;35:1661-72.
21. Jane DE, Thomas NK, Tse HW, et al. Potent antagonists at the L-AP4- and (1S,3S)-ACPD-sensitive presynaptic metabotropic glutamate receptors in the neonatal rat spinal cord. Neuropharmacology 1996;35:1029-35.
22. Wermuth CG, Mann A, Schoenfelder A, et al. (2S,4S)-2-amino-4-(4,4-diphenylbut-1-yl)- pentane-1,5-dioic acid: a potent and selective antagonist for metabotropic glutamate receptors negatively linked to adenylate cyclase. J Med Chem 1996;39:814-6.
23. Escribano A, Ezquerra J, Pedregal C, et al. (2S,4S)-amino-4-(2,2-diphenylethyl)pentanedioic acid selective group 2 metabotropic glutamate receptor antagonist. Bioorg Med Chem Lett 1998;8:765-70.
24. Gasparini F, Bruno V, Battaglia G, et al. (R,S)-4-phosphonophenylglycine, a potent and selective group III metabotropic glutamate receptor agonist is anticonvulsive and neuroprotectivein vivo. J Pharmacol Exp Ther 1999;289:1678-1687.
25. Kingston AE, Ornstein PL, Wright RA, et al. LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors. Neuropharmacology 1998;37:1-12.

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