Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

Urwyler, Stephan

doi:10.1124/pr.109.002501

Cited by 187 publications

(180 citation statements)

References 474 publications

(578 reference statements)

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“…The 7TM is the target of a number of synthetic compounds acting either as negative or positive allosteric modulators (NAMs and PAMs, respectively). Given their ability to finely tune endogenous signaling, such compounds present exciting opportunities for drug development (10).…”

mentioning

confidence: 99%

Distinct roles of metabotropic glutamate receptor dimerization in agonist activation and G-protein coupling

Moustaine

Granier

Doumazane

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

151

133

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The eight metabotropic glutamate receptors (mGluRs) are key modulators of synaptic transmission and are considered promising targets for the treatment of various brain disorders. Whereas glutamate acts at a large extracellular domain, allosteric modulators have been identified that bind to the seven transmembrane domain (7TM) of these dimeric G-protein-coupled receptors (GPCRs). We show here that the dimeric organization of mGluRs is required for the modulation of active and inactive states of the 7TM by agonists, but is not necessary for G-protein activation. Monomeric mGlu2, either as an isolated 7TM or in full-length, purified and reconstituted into nanodiscs, couples to G proteins upon direct activation by a positive allosteric modulator. However, only a reconstituted full-length dimeric mGlu2 activates G protein upon glutamate binding, suggesting that dimerization is required for glutamate induced activation. These data show that, even for such well characterized GPCR dimers like mGluR2, a single 7TM is sufficient for G-protein coupling. Despite this observation, the necessity of dimeric architecture for signaling induced by the endogenous ligand glutamate confirms that the central core of signaling complex is dimeric.M etabotropic glutamate receptors (mGluRs) play key roles in the modulation of both excitatory and inhibitory synapses in the brain. These eight G-protein-coupled receptors (GPCRs) represent major targets for pharmaceutical companies in search of new treatments for a variety of neurological and psychiatric disorders (1-3). These receptors are part of the class C GPCR family that also includes the GABA B , calcium sensing, and sweet and umami taste receptors, which are all major targets for drug development (4).The structural complexity of class C GPCRs, compared with rhodopsin-like class A GPCRs, offers multiple possibilities in designing molecules that modulate their activity. Not only are mGluRs strict constitutive dimers (5, 6), but each protomer is composed of several domains (7,8). Agonists bind in a bilobate venus fly-trap domain (VFT) (9), which is linked through a cysteine-rich domain (CRD) to the heptahelical transmembrane domain (7TM) that is responsible for G-protein activation (7). The 7TM is the target of a number of synthetic compounds acting either as negative or positive allosteric modulators (NAMs and PAMs, respectively). Given their ability to finely tune endogenous signaling, such compounds present exciting opportunities for drug development (10).The functional mechanism of such a complex machine remains to be characterized, although some critical steps have been well documented. Previous studies have shown that receptor activation results from the closure of the VFT upon agonist binding (9,(11)(12)(13)(14)(15). This conformational change in the extracellular domain is coupled to a conformational change in the intracellular side of at least one 7TM that is responsible for G-protein coupling (16)(17)(18)(19). The mechanism for allosteric communication between the VFT and 7TM ...

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mentioning

confidence: 99%

Distinct roles of metabotropic glutamate receptor dimerization in agonist activation and G-protein coupling

Moustaine

Granier

Doumazane

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

151

133

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“…It has been reported recently that several amino acids [89,90] and Ca 2+ [91,92] can modulate GABA B receptor function via a conserved pocket that is located near the orthosteric sites, which is reminiscent of the modulation that has been observed for mGlu-like receptors. Unfortunately, animal models suggest that the existing allosteric modulators for the GABA B receptor are not suitable for clinical use due to their low potency and unfavorable pharmacokinetic properties [5] . Therefore, it is necessary to identify new allosteric sites on the GABA B receptor that may lead to the discovery of new types of therapeutic ligands.…”

Section: Gaba B Receptors -The Unique Pam Cgp7930mentioning

confidence: 99%

“…Class C GPCRs are composed of metabotropic glutamate receptors (mGlu receptors), γ-aminobutyric acid B receptors (GABA B receptors), Ca 2+ -sensing receptors (CaS receptors), sweet and amino acid taste receptors, pheromone receptors, odorant receptors in fish and several orphan receptors [3] . mGlu, GABA B , and CaS receptors represent an important new class of therapeutic targets that are integral to disorders that affect the central neural system (CNS) and calcium homeostasis [4,5] . The taste receptors, on the other hand, attract significant attention from food companies because the taste additives that target these receptors represent a key feature of the large food industry market [5] .…”

Section: Introductionmentioning

confidence: 99%

“…mGlu, GABA B , and CaS receptors represent an important new class of therapeutic targets that are integral to disorders that affect the central neural system (CNS) and calcium homeostasis [4,5] . The taste receptors, on the other hand, attract significant attention from food companies because the taste additives that target these receptors represent a key feature of the large food industry market [5] .…”

Section: Introductionmentioning

confidence: 99%

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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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“…The latter represent the largest class of cell surface proteins and the major receptor class for neuropeptides including GABA receptors [13][14][15] .…”

Section: Wwwchinapharcom Bartfai T Et Almentioning

confidence: 99%

Positive allosteric modulators to peptide GPCRs: a promising class of drugs

Bartfai

Wang

2013

Acta Pharmacol Sin

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The task of finding selective and stable peptide receptor agonists with low molecular weight, desirable pharmacokinetic properties and penetrable to the blood-brain barrier has proven too difficult for many highly coveted drug targets, including receptors for endothelin, vasoactive intestinal peptide and galanin. These receptors and ligand-gated ion channels activated by structurally simple agonists such as glutamate, glycine and GABA present such a narrow chemical space that the design of subtype-selective molecules capable of distinguishing a dozen of glutamate and GABA receptor subtypes and possessing desirable pharmacokinetic properties has also been problematic. In contrast, the pharmaceutical industry demonstrates a remarkable success in developing 1,4-benzodiazepines, positive allosteric modulators (PMAs) of the GABA A receptor. They were synthesized over 50 years ago and discovered to have anxiolytic potential through an in vivo assay. As exemplified by Librium, Valium and Dormicum, these allosteric ligands of the receptor became the world's first blockbuster drugs. Through molecular manipulation over the past 2 decades, including mutations and knockouts of the endogenous ligands or their receptors, and by in-depth physiological and pharmacological studies, more peptide and glutamate receptors have become well-validated drug targets for which an agonist is sought. In such cases, the pursuit for PAMs has also intensified, and a working paradigm to identify drug candidates that are designed as PAMs has emerged. This review, which focuses on the general principles of finding PAMs of peptide receptors in the 21st century, describes the workflow and some of its resulting compounds such as PAMs of galanin receptor 2 that act as potent anticonvulsant agents.

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Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

Cited by 187 publications

References 474 publications

Distinct roles of metabotropic glutamate receptor dimerization in agonist activation and G-protein coupling

Distinct roles of metabotropic glutamate receptor dimerization in agonist activation and G-protein coupling

Structure and ligand recognition of class C GPCRs

Positive allosteric modulators to peptide GPCRs: a promising class of drugs

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