Ginger and its pungent constituents non‐competitively inhibit activation of human recombinant and native 5‐HT<sub>3</sub> receptors of enteric neurons

Walstab, Jutta; Krüger, D.; Stark, Timo D.; Hofmann, Thomas; Demir, Ihsan Ekin; Ceyhan, Güralp O.; Feistel, B; Schemann, Michael; Niesler, Beate

doi:10.1111/nmo.12107

Cited by 72 publications

(66 citation statements)

References 40 publications

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“…These results were corroborated by an in vitro study by Walstab et al [10] which indicated that ginger was able to inhibit the activation of human 5-HT3 receptors and that this was likely via noncompetitive mechanisms. Additionally, since pre-incubation with 6G produced increased inhibition it was proposed that its binding site may be relatively inaccessible such as that of the transmembrane channel.…”

Section: Introductionsupporting

confidence: 78%

“…Ginger ligands formed hydrogen bonds with several residues, predominantly R65, T154 and N101. We found previously unidentified residue, E102, contributed to stabilization of [10]-dehydroshogaol. The setron group of ligands docked into two main regions within the site.…”

Section: Serotonin Binding Site Resultsmentioning

confidence: 90%

“…[10] The subunits in the functioning unit are either arranged homo or heteromerically around a cation-specific, water filled central pore. Only the A subunit has been shown to form functional homomeric receptors and, importantly, the presence of the A subunit was required in all receptors.…”

Section: Introductionmentioning

confidence: 99%

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In silico investigation into the interactions between murine 5-HT3 receptor and the principle active compounds of ginger (Zingiber officinale)

Lohning

Marx

Isenring

2016

Journal of Molecular Graphics and Modelling

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. In silico investigation into the interactions between murine 5-HT3 receptor and the principle active compounds of ginger (Zingiber officinale).. Retrieved from http://dx.doi. org/10.1016/j.jmgm.2016.10.008 1 Abstract Gingerols and shogaols are the primary non-volatile actives within ginger (Zingiber officinale).These compounds have demonstrated in vitro to exert 5-HT3 receptor antagonism which could benefit chemotherapy-induced nausea and vomiting (CINV). The site and mechanism of action by which these compounds interact with the 5-HT3 receptor is not fully understood although research indicates they may bind to a currently unidentified allosteric binding site. Using in silico techniques, such as molecular docking and GRID analysis, we have characterized the recently available murine 5-HT3 receptor by identifying sites of strong interaction with particular functional groups at both the orthogonal (serotonin) site and a proposed allosteric binding site situated at the interface between the transmembrane region and the extracellular domain. These were assessed concurrently with the top-scoring poses of the docked ligands and included key active gingerols, shogaols and dehydroshogaols as well as competitive antagonists (e.g. setron class of pharmacologically active drugs), serotonin and its structural analogues, curcumin and capsaicin, non-competitive antagonists and decoys. Unexpectedly, we found that the ginger compounds and their structural analogs generally outscored other ligands at both sites. Our results correlated well with previous site-directed mutagenesis studies in identifying key binding site residues. We have identified new residues important for binding the ginger compounds. Overall, the results suggest that the ginger compounds and their structural analogues possess a high binding affinity to both sites. Notwithstanding the limitations of such theoretical analyses, these results suggest that the ginger compounds could act both competitively or non-competitively as has been shown for palonosetron and other modulators of CYS loop receptors. KeywordsGinger antiemetic Zingiber officinale gingerol shogaols chemotherapy induced nausea vomiting 2

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Section: Introductionsupporting

confidence: 78%

Section: Serotonin Binding Site Resultsmentioning

confidence: 90%

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In silico investigation into the interactions between murine 5-HT3 receptor and the principle active compounds of ginger (Zingiber officinale)

Lohning

Marx

Isenring

2016

Journal of Molecular Graphics and Modelling

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“…Data sets were tested for statistically significant differences using Student's t-test from SigmaPlot 8.0 and were corrected for multiple parallel tests using the Bonferroni method. (6S)-Gingerol ((S)-5-hydroxy-1-(4-hydroxy-3-methoxy-phenyl)-decan-3-one) was isolated as has been recently described [11]. 6-Shogaol, 4-methyl-(6S)-gingerol, (6S)-gingerol-4-O-β-Dglucuronide and (6S)-gingerdiol ((5S)-1-(4-hydroxy-3-methoxy-phenyl)-decan-3,5-diole) were synthesized using isolated (6S)-gingerol and following the procedures previously described described [12][13][14].…”

Section: Discussionmentioning

confidence: 99%

“…Ginger (Zingiber officinale) has been shown to exert anti-emetic properties [20,21], and some M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT of its ingredients, such as 6-gingerol and 6-shogaol, have been shown to inhibit 5-HT 3A receptor function in a calcium imaging assay [11]. Gingerols, shogaols and capsaicin from the chili pepper are chemically related vanilloid substances.…”

Section: Action Of Pungent Substancesmentioning

confidence: 99%

Activation and modulation of recombinantly expressed serotonin receptor type 3A by terpenes and pungent substances

Ziemba

Schreiner

Flegel

et al. 2015

Biochemical and Biophysical Research Communications

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The Human Serotonin Type 3 Receptor Gene (HTR3A-E) Allelic Variant Database

2016

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Serotonin type 3 (5-HT ) receptors are ligand-gated ion channels formed by five subunits (5-HT3A-E), which are encoded by the HTR3A, HTR3B, HTR3C, HTR3D, and HTR3E genes. Functional receptors are pentameric complexes of diverse composition. Different receptor subtypes confer a predisposition to nausea and vomiting during chemotherapy, pregnancy, and following surgery. In addition, different subtypes contribute to neurogastroenterologic disorders such irritable bowel syndrome (IBS) and eating disorders as well as comorbid psychiatric conditions. 5-HT receptor antagonists are established treatments for emesis and IBS and are beneficial in the treatment of psychiatric diseases. Several case-control and pharmacogenetic studies have demonstrated an association between HTR3 variants and psychiatric and neurogastroenterologic phenotypes. Recently, their potential as predictors of nausea and vomiting and treatment of psychiatric disorders became evident. This information is now available in the serotonin receptor 3 HTR3 gene allelic variant database (www.htr3.uni-hd.de), which contains five sub-databases, one for each of the five different serotonin receptor genes HTR3A-E. Information on HTR3 variants, their functional relevance, associated phenotypes, and pharmacogenetic data such as drug response and side effects are available. This central information pool should help clinicians as well as scientists to evaluate their findings and to use the relevant information for subsequent genotype-phenotype correlation studies and pharmacogenetic approaches.

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Ginger and its pungent constituents non‐competitively inhibit activation of human recombinant and native 5‐HT₃ receptors of enteric neurons

Abstract: Our findings may encourage the use of ginger extracts to alleviate nausea in cancer patients receiving chemotherapy and to treat functional GI disorders.

Cited by 72 publications

References 40 publications

In silico investigation into the interactions between murine 5-HT3 receptor and the principle active compounds of ginger (Zingiber officinale)

In silico investigation into the interactions between murine 5-HT3 receptor and the principle active compounds of ginger (Zingiber officinale)

Activation and modulation of recombinantly expressed serotonin receptor type 3A by terpenes and pungent substances

The Human Serotonin Type 3 Receptor Gene (HTR3A-E) Allelic Variant Database

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Ginger and its pungent constituents non‐competitively inhibit activation of human recombinant and native 5‐HT3 receptors of enteric neurons

Abstract: Our findings may encourage the use of ginger extracts to alleviate nausea in cancer patients receiving chemotherapy and to treat functional GI disorders.

Cited by 72 publications

References 40 publications

In silico investigation into the interactions between murine 5-HT3 receptor and the principle active compounds of ginger (Zingiber officinale)

In silico investigation into the interactions between murine 5-HT3 receptor and the principle active compounds of ginger (Zingiber officinale)

Activation and modulation of recombinantly expressed serotonin receptor type 3A by terpenes and pungent substances

The Human Serotonin Type 3 Receptor Gene (HTR3A-E) Allelic Variant Database

Contact Info

Product

Resources

About

Ginger and its pungent constituents non‐competitively inhibit activation of human recombinant and native 5‐HT₃ receptors of enteric neurons