ReviewBinding properties between human sweet receptor and sweet-inhibitor, gymnemic acids
Introduction
Humans perceive sweet taste to detect carbohydrates, which are a source of calories. The sweet taste signal conveyed to the brain is thought to play an important role in energy homeostasis. The TAS1R2+TAS1R3 heterodimer may be the sole receptor detecting sweet taste signals in taste bud cells embedded in the oral cavity (Fig. 1A). Previous studies using HEK293 cells demonstrated that the TAS1R2+TAS1R3 receptor can broadly respond to a variety of sweet chemicals including not only sugars, but also amino acids, peptides, proteins, and even artificial sweeteners that can bind the receptor molecules at different sites. Human psychophysical studies have shown that two chemical compounds, gymnemic acids (GAs) and lactisole, can act as sweet taste inhibitors to inhibit perceived sweetness, including for sweet chemicals with different chemical structures [1], [2], [3], [4]. Therefore, the potential binding sites of the inhibitors on the sweet receptor and the mechanism by which these inhibitors block the activation of the receptor in response to a variety of sweet chemicals with different binding sites should be determined.
GAs, which are saponins of triterpene glycoside, are sweet inhibitors present in the leaves of the plant Gymnema sylvestre; this plant is native to central and western India (Fig. 1B). GAs are composed of several types of homologs and selectively suppress sweet taste responses for 30–60 min without affecting the responses to salty, sour, and bitter compounds [1], [2], [3]. The sweet-suppressing effect of GAs is specific to humans and chimpanzees, but does not occur in rodents and is diminished by the application of γ-cyclodextrin (CD) to the tongue [5], [6], [7], [8], [9]. GAs are also known to inhibit intestinal glucose absorption and reduce plasma glucose and insulin levels [10], [11], [12].
In this review, we focus on the molecular mechanisms underlying the interaction between the sweet receptor and GAs.
Section snippets
Sweet receptor
Sweet substances are detected by the TAS1R family belonging to class C G-protein coupled receptors, including the metabotropic glutamate receptors, calcium-sensing receptor, and other taste/olfactory receptors [13], [14], [15], [16], [17], [18], [19], [20], [21]. TAS1R2 and TAS1R3 form a heterodimeric complex to function as a sweet taste receptor. Based on sequence similarity, the structures of TAS1Rs consist of three major domains: a large extracellular amino-terminal domain (ATD),
Interaction site for GAs
We first examined whether GAs directly interact with the human sweet receptor by conducting a sweet receptor assay in HEK293 cells transiently expressing hTAS1R2, hTAS1R3, and Gα16-gust44 [31]. We monitored [Ca2+]i responses to various sweet substances such as SC45647, saccharin, aspartame, cyclamate, D-tryptophan, and sucrose [31]. Calcium responses to these substances were reduced or completely absent after the application of GAs, indicating the sweet-suppressing effect of GAs. GAs did not
Conclusion
Our study demonstrated the molecular mechanisms of the sweet-suppressing effects of GAs. GAs and glucuronic acid directly inhibit the human sweet receptor TAS1R2+TAS1R3. The interaction between GAs and the sweet receptor is diminished by applying γ-CD, which forms complexes with GAs. The TMD of hTAS1R3 is the main domain determining the sensitivity to GAs. The glucuronosyl group on GAs plays an important role in its sweet-suppressing effect.
Recently, the sweet taste receptor was reported to be
Ethical approval
All experimental procedures were approved by the animal care and use committee of Kyushu University.
Conflict of interest
The authors declare no competing financial interests.
Acknowledgements
We thank Dr. Gary Beauchamp (Monell Chemical Senses Center), Dr. Ryusuke Yoshida (Kyushu University), Dr. Yuko Kusakabe (National Food Research Institute), Dr. Takatsugu Hirokawa (National Institute of Advanced Industrial Science and Technology), Toshiaki Imoto (Tottori University), and Dr. Seiji Nakamura (Kyushu University) for their valuable suggestions on the manuscript. We also thank Dr. Kazushige Touhara (University of Tokyo) for technical advice on Ca2+ imaging and Dr. Makoto Tominaga
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