Positive allosteric modulators of metabotropic glutamate 1 receptor: Characterization, mechanism of action, and binding site

Knoflach, Frédéric; Mutel, Vincent; Jolidon, Synèse; Kew, James N.C.; Malherbe, Pari; Vieira, Eric; Wichmann, Jürgen; Kemp, John A.

doi:10.1073/pnas.231358298

Cited by 225 publications

(223 citation statements)

References 27 publications

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“…Positive allosteric modulators have been identified for other family 3 GPCR such as mGluR1 (12) and GABA B receptor (28). The site of action for the latter was not defined, but for positive allosteric modulators of mGluR1, residues in the third and fifth transmembrane helices of the 7TM domain were shown to be critical for selective response (12).…”

Section: Immunocytochemistry Of Cells Expressing Rho-c-hcar/5amentioning

confidence: 99%

“…The activation of family 3 GPCR can also be positively modulated by compounds that bind to the 7TM domain and are presumed to act allosterically (12). The phenylalkylamine, NPS R-568, a so-called calcimimetic, increases the sensitivity of the receptor to [Ca 2ϩ ] o activation (13), acting as a positive allosteric modulator by binding to the CaR 7TM region (14).…”

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confidence: 99%

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Identification of Acidic Residues in the Extracellular Loops of the Seven-transmembrane Domain of the Human Ca2+ Receptor Critical for Response to Ca2+ and a Positive Allosteric Modulator

Reyes‐Cruz

Chen

et al. 2002

Journal of Biological Chemistry

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We investigated the role of the eight acidic residues in the extracellular loops (exo-loops) of the seven-transmembrane domain of the human Ca 2؉ receptor (hCaR) in receptor activation by Ca 2؉ and in response to a positive allosteric modulator, NPS R-568. Both in the context of the full-length receptor and of a truncated receptor lacking the extracellular domain (Rho-C-hCaR), we mutated each acidic residue to alanine, singly and in combination, and tested the effect on expression of the receptor, on activation by Ca 2؉ , and on NPS R-568 augmentation of sensitivity to Ca 2؉ . Of the eight acidic residues, mutation of any of three in exo-loop 2, Asp 758 , Glu 759 , and Glu 767 , increased the sensitivity of both the full-length hCaR and of Rho-C-hCaR to activation by Ca 2؉ . Mutation of all five acidic residues in exo-loop 2, whether in the full-length receptor or in Rho-C-hCaR, impaired cell surface expression of the mutant receptor and thereby largely abolished response to Ca 2؉ . Mutation of Glu 837 in exo-loop 3 to alanine did not alter Ca 2؉ sensitivity of the full-length receptor, but in both the latter context and in Rho-C-hCaR, alanine substitution of Glu 837 drastically reduced sensitivity to NPS R-568. Our data point to a key role of three specific acidic residues in exo-loop 2 in hCaR activation and to Glu 837 at the junction between exo-loop 3 and transmembrane helix seven in response to NPS R-568. We speculate on the basis of these results that the three acidic residues we identified in exo-loop 2 help maintain an inactive conformation of the seven-transmembrane domain of the hCaR.The G protein-coupled [Ca 2ϩ ] o receptor (CaR) 1 plays a central role in the regulation of [Ca 2ϩ ] o homeostasis (1, 2). [Ca 2ϩ ] o activates the CaR in the parathyroid, thereby inhibiting parathyroid hormone secretion, and in the kidney, causing increased urinary calcium excretion. The physiological importance of the CaR in determining the level at which [Ca 2ϩ ] o is set in vivo has been documented by the identification of inactivating mutations in the CaR gene as the cause of familial hypocalciuric hypercalcemia and activating mutations as the cause of autosomal dominant hypocalcemia (3, 4). Naturally occurring CaR mutations identified in subjects with autosomal dominant hypocalcemia generally cause increased CaR sensitivity to [Ca 2ϩ ] o rather than causing constitutive activation (5).The CaR belongs to a unique subfamily, family 3, of G protein-coupled receptors (GPCR) with an unusually large N-terminal, extracellular domain (ECD) comprised of Venus's-flytrap (VFT) and cysteine-rich domains, in addition to the seventransmembrane domain (7TM) characteristic of all GPCR (6). Studies with chimeric family 3 GPCR (7-10) and the threedimensional structure of the metabotropic glutamate type 1 receptor (mGluR1) determined by x-ray crystallography (11) show that the VFT is the site of agonist binding in family 3 GPCR. The precise site(s) for binding to the CaR, however, have not been identified.The activation of family ...

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Section: Immunocytochemistry Of Cells Expressing Rho-c-hcar/5amentioning

confidence: 99%

mentioning

confidence: 99%

Identification of Acidic Residues in the Extracellular Loops of the Seven-transmembrane Domain of the Human Ca2+ Receptor Critical for Response to Ca2+ and a Positive Allosteric Modulator

Reyes‐Cruz

Chen

et al. 2002

Journal of Biological Chemistry

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“…Binding of a negative allosteric modulator to this site results in non-competitive inhibition of the receptor. Positive allosteric modulators do not activate the receptor, but can change the EC50 for an orthosteric agonist or increase its maximum effect (Ellaithy et al 2015;Kinney et al 2005;Knoflach et al 2001;Layton 2005;Sengmany et al 2017). The history of mGlu receptor pharmacology and drug development, as well as comprehensive lists of disclosed compounds with orthosteric or allosteric activity, is well documented (Alexander et al 2011;Ferraguti et al 2008;Pin et al 1999;Schoepp et al 1999).…”

Section: Pharmacologymentioning

confidence: 99%

Control of neuronal excitability by Group I metabotropic glutamate receptors

Amb

Jds

et al. 2017

Biophys Rev

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Metabotropic glutamate (mGlu) receptors couple through G proteins to regulate a large number of cell functions. Eight mGlu receptor isoforms have been cloned and classified into three Groups based on sequence, signal transduction mechanisms and pharmacology. This review will focus on Group I mGlu receptors, comprising the isoforms mGlu 1 and mGlu 5 . Activation of these receptors initiates both G protein-dependent and -independent signal transduction pathways. The G-protein-dependent pathway involves mainly Gα q , which can activate PLCβ, leading initially to the formation of IP 3 and diacylglycerol. IP 3 can release Ca 2+ from cellular stores resulting in activation of Ca 2+ -dependent ion channels. Intracellular Ca 2+ , together with diacylglycerol, activates PKC, which has many protein targets, including ion channels. Thus, activation of the G-protein-dependent pathway affects cellular excitability though several different effectors. In parallel, G protein-independent pathways lead to activation of non-selective cationic currents and metabotropic synaptic currents and potentials. Here, we provide a survey of the membrane transport proteins responsible for these electrical effects of Group I metabotropic glutamate receptors.

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“…For the mGlu5 receptor, most PAMs and NAMs share an overlapping binding pocket that is composed of TM3, 5, 6, and 7 [73] , except for a small number of distinct sites [74] . For the mGlu1 receptor, however, the PAMs and NAMs bind to distinct sites in the 7TM [64,65,[75][76][77] , except for a shared site that consists of Val757 in TM3 [65,77] . Removed from the conserved binding pocket, there is a distinct allosteric site located in TM1.…”

Section: Ligand Binding Sites Of Four Typical Class C Gpcr Family Memmentioning

confidence: 99%

Structure and ligand recognition of class C GPCRs

2012

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The G-protein-coupled receptors (GPCRs) are one of the largest super families of cell-surface receptors and play crucial roles in virtually every organ system. One particular family of GPCRs, the class C GPCRs, is distinguished by a characteristically large extracellular domain and constitutive dimerization. The structure and activation mechanism of this family result in potentially unique ligand recognition sites, thereby offering a variety of possibilities by which receptor activity might be modulated using novel compounds. In the present article, we aim to provide an overview of the exact sites and structural features involved in ligand recognition of the class C GPCRs. Furthermore, we demonstrate the precise steps that occur during the receptor activation process, which underlie the possibilities by which receptor function may be altered by different approaches. Finally, we use four typical family members to illustrate orthosteric and allosteric sites with representative ligands and their corresponding therapeutic potential.

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Positive allosteric modulators of metabotropic glutamate 1 receptor: Characterization, mechanism of action, and binding site

Cited by 225 publications

References 27 publications

Identification of Acidic Residues in the Extracellular Loops of the Seven-transmembrane Domain of the Human Ca2+ Receptor Critical for Response to Ca2+ and a Positive Allosteric Modulator

Identification of Acidic Residues in the Extracellular Loops of the Seven-transmembrane Domain of the Human Ca2+ Receptor Critical for Response to Ca2+ and a Positive Allosteric Modulator

Control of neuronal excitability by Group I metabotropic glutamate receptors

Structure and ligand recognition of class C GPCRs

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