title: Molecular mechanisms for sweet-suppressing effect of gymnemic acids.
abstract: Gymnemic acids are triterpene glycosides that selectively suppress taste responses to various sweet substances in humans but not in mice. This sweet-suppressing effect of gymnemic acids is diminished by rinsing the tongue with γ-cyclodextrin (γ-CD). However, little is known about the molecular mechanisms underlying the sweet-suppressing effect of gymnemic acids and the interaction between gymnemic acids versus sweet taste receptor and/or γ-CD. To investigate whether gymnemic acids directly interact with human (h) sweet receptor hT1R2 + hT1R3, we used the sweet receptor T1R2 + T1R3 assay in transiently transfected HEK293 cells. Similar to previous studies in humans and mice, gymnemic acids (100 μg/ml) inhibited the [Ca(2+)]i responses to sweet compounds in HEK293 cells heterologously expressing hT1R2 + hT1R3 but not in those expressing the mouse (m) sweet receptor mT1R2 + mT1R3. The effect of gymnemic acids rapidly disappeared after rinsing the HEK293 cells with γ-CD. Using mixed species pairings of human and mouse sweet receptor subunits and chimeras, we determined that the transmembrane domain of hT1R3 was mainly required for the sweet-suppressing effect of gymnemic acids. Directed mutagenesis in the transmembrane domain of hT1R3 revealed that the interaction site for gymnemic acids shared the amino acid residues that determined the sensitivity to another sweet antagonist, lactisole. Glucuronic acid, which is the common structure of gymnemic acids, also reduced sensitivity to sweet compounds. In our models, gymnemic acids were predicted to dock to a binding pocket within the transmembrane domain of hT1R3.
authors: From the Section of Oral Neuroscience, Oral and Maxillofacial Oncology, Graduate School of Dental Sciences, and.
authors: Keisuke
authors: K
authors: Sanematsu
authors: Sensory and Cognitive Food Sciences, National Food Research Institute, Tsukuba 305-8642.
authors: Yuko
authors: Y
authors: Kusakabe
authors: From the Section of Oral Neuroscience.
authors: Noriatsu
authors: N
authors: Shigemura
authors: the National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, and.
authors: Takatsugu
authors: T
authors: Hirokawa
authors: Oral and Maxillofacial Oncology, Graduate School of Dental Sciences, and.
authors: Seiji
authors: S
authors: Nakamura
authors: the Division of Integrative Physiology, Department of Functional, Morphological and Regulatory Science, Tottori University, Yonago 683-8503, Japan.
authors: Toshiaki
authors: T
authors: Imoto
authors: From the Section of Oral Neuroscience, Division of Sensory Physiology, Research and Development Center for Taste and Odor Sensing, Kyushu University, Fukuoka 812-8582, yuninom@dent.kyushu-u.ac.jp.
authors: Yuzo
authors: Y
authors: Ninomiya
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001555:Benzene Derivatives / Q000008:administration & dosage; D001665:Binding Sites; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D012503:Saponins / Q000008:administration & dosage*; D013549:Sweetening Agents / Q000008:administration & dosage*; D013649:Taste / Q000187:drug effects / Q000235:genetics*; D013650:Taste Buds / Q000187:drug effects* / Q000378:metabolism; D014315:Triterpenes / Q000008:administration & dosage*
chemical_list: D001555:Benzene Derivatives; D043562:Receptors, G-Protein-Coupled; D012503:Saponins; D013549:Sweetening Agents; D014315:Triterpenes; C431926:taste receptors, type 1; C007898:gymnemic acid; C495512:lactisole
keywords: Calcium Imaging; G Protein-coupled Receptor; Gymnemic Acids; Molecular Evolution; Molecular Modeling; Signal Transduction; Sweet Taste; T1R2 + T1R3