Structure, Pharmacology and Therapeutic Prospects of Family C G-Protein Coupled Receptors

Bräuner‐Osborne, Hans; Wellendorph, Petrine; Jensen, Anders A.

doi:10.2174/138945007779315614

Cited by 223 publications

(184 citation statements)

References 3 publications

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“…We have developed a very sensitive cell-based assay for the detection of human sweet taste receptor modulators. In this assay system, the human sweet taste receptor couples to the promiscuous G protein Gα 15 to induce PLC Author contributions: G.S., C.T., and X.L. designed research; X.-Q.T., S.W., F.Z., P.K., G.P., A.J., P.B., and N.B.…”

Section: Resultsmentioning

confidence: 99%

“…Multiple PAMs have been identified for the mGluRs, the GABA B receptor, and the calcium sensing receptor (15,16), and they all bind to the TMD. In contrast, hits that interact with the TMD of sweet taste receptor are agonists (10,18).…”

Section: Resultsmentioning

confidence: 99%

“…The savory (umami) taste receptor, a close relative to the human sweet taste receptor, is significantly enhanced by 5′-ribonucleotides (6,14). Positive allosteric modulators (PAMs) have also been identified for the GABA B receptor, the calcium sensing receptor, and several subtypes of the metabotropic glutamate receptor (mGluR) family (15,16). In all cases, the PAMs show little or no agonist activity on their own but significantly enhance the activity of the agonist on the receptor and, in functional assays, this behavior is depicted by a leftward shift of the agonist doseresponse in the presence of the PAM (16)(17)(18).…”

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confidence: 99%

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Positive allosteric modulators of the human sweet taste receptor enhance sweet taste

Servant¹,

Tachdjian²,

Tang³

et al. 2010

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

119

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To identify molecules that could enhance sweetness perception, we undertook the screening of a compound library using a cellbased assay for the human sweet taste receptor and a panel of selected sweeteners. In one of these screens we found a hit, SE-1, which significantly enhanced the activity of sucralose in the assay. At 50 μM, SE-1 increased the sucralose potency by >20-fold. On the other hand, SE-1 exhibited little or no agonist activity on its own. SE-1 effects were strikingly selective for sucralose. Other popular sweeteners such as aspartame, cyclamate, and saccharin were not enhanced by SE-1 whereas sucrose and neotame potency were increased only by 1.3-to 2.5-fold at 50 μM. Further assayguided chemical optimization of the initial hit SE-1 led to the discovery of SE-2 and SE-3, selective enhancers of sucralose and sucrose, respectively. SE-2 (50 μM) and SE-3 (200 μM) increased sucralose and sucrose potencies in the assay by 24-and 4.7-fold, respectively. In human taste tests, 100 μM of SE-1 and SE-2 allowed for a reduction of 50% to >80% in the concentration of sucralose, respectively, while maintaining the sweetness intensity, and 100 μM SE-3 allowed for a reduction of 33% in the concentration of sucrose while maintaining the sweetness intensity. These enhancers did not exhibit any sweetness when tasted on their own. Positive allosteric modulators of the human sweet taste receptor could help reduce the caloric content in food and beverages while maintaining the desired taste.enhancer | sweetness | perception | sucrose T he steady increase of the daily consumption of dietary sugar over the last decades may have contributed to the obesity crisis and the early onset of type-II diabetes observed in many developed countries (1, 2). As a result, food and beverage companies have launched a plethora of diet brands where sugar has been partly or fully replaced by noncaloric sweeteners to decrease caloric intake. Currently some of the commonly used noncaloric sweeteners include saccharin, aspartame, cyclamate, sucralose, and acesulfame K (3, 4). However, none of these substances can completely reproduce the taste of sugar. These sweeteners all suffer from one or more shortcomings including a bitter or metallic aftertaste at high concentrations, limiting their use to lower concentrations, or temporal issues such as a delayed sweet taste onset, a lingering sweet aftertaste, or a limited maximum sweetness intensity (4, 5). Another appealing approach to address the problem, in addition to looking for novel noncaloric sweeteners, would be to find molecules capable of enhancing sweetness perception. Ideally, such an enhancer molecule would not elicit sweetness on its own but it would boost the sweetness intensity of a lower amount of sweetener or sugar. Such enhancers could therefore allow for a reduction in the amount of sugar, and calories, in food and beverages while maintaining the desired taste. Similarly, a sweet taste enhancer could allow for a reduction in the amount of noncaloric sweeteners used in "0"-calorie...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Positive allosteric modulators of the human sweet taste receptor enhance sweet taste

Servant¹,

Tachdjian²,

Tang³

et al. 2010

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

119

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“…They are obligate dimers, activated by glutamate 9 , the major excitatory neurotransmitter in the central nervous system, and they are essential to the regulation of synaptic activity 10 , representing, therefore, promising targets in drug development 11 . The eight mGluR subtypes belong to the class C GPCR family, which also includes the receptors for GABA, calcium and for the flavours sweet and umami 12,13 . These receptors share a large extracellular ligandbinding domain (ECD), and a heptahelical transmembrane domain (7TM) responsible for G-protein activation (Fig.…”

mentioning

confidence: 99%

Fine tuning of sub-millisecond conformational dynamics controls metabotropic glutamate receptors agonist efficacy

et al. 2014

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Efficient cell-to-cell communication relies on the accurate signalling of cell surface receptors. Understanding the molecular bases of their activation requires the characterization of the dynamic equilibrium between active and resting states. Here, we monitor, using single-molecule Förster resonance energy transfer, the kinetics of the reorientation of the extracellular ligand-binding domain of the metabotropic glutamate receptor (mGluR), a class C G-protein-coupled receptor. We demonstrate that most receptors oscillate between a resting-and an active-conformation on a sub-millisecond timescale. Interestingly, we demonstrate that differences in agonist efficacies stem from differing abilities to shift the conformational equilibrium towards the fully active state, rather than from the stabilization of alternative static conformations, which further highlights the dynamic nature of mGluRs and revises our understanding of receptor activation and allosteric modulation.

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“…Acta Pharmacologica Sinica npg is conserved and is formed by residues in TM3, 5, 6, and 7, which correspond to orthosteric sites within the 7TM of rhodopsin-like receptors [3,59] . Many allosteric modulators for class C GPCRs have been demonstrated to bind in this pocket.…”

Section: Tm Allosteric Sitesmentioning

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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Structure, Pharmacology and Therapeutic Prospects of Family C G-Protein Coupled Receptors

Cited by 223 publications

References 3 publications

Positive allosteric modulators of the human sweet taste receptor enhance sweet taste

Positive allosteric modulators of the human sweet taste receptor enhance sweet taste

Fine tuning of sub-millisecond conformational dynamics controls metabotropic glutamate receptors agonist efficacy

Structure and ligand recognition of class C GPCRs

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