Kyudai News No26 page 12/28

Description:
Kyudai News No26

11 Kyudai News No.26 ymnemic acids are triterpene glycosides thatare derived from the plant Gymnema sylvestreand are known to selectively suppress thesensation of sweetness in humans. However, themolecular mechanism of this suppression was unknown.Taking advantage of the fact that there are speciesdifferences in the effects of gymnemic acids (which areineffective in mice), we reconstructed the human andmouse versions of the sweet taste receptors T1R2/T1R3 anda chimera of the two in HEK cells and investigated theinteraction between gymnemic acids and each version ofT1R2/T1R3. As a result, we ascertained that there is aspecies difference in the features of receptor binding,because gymnemic acids suppressed the sweetnessresponse in the human T1R2/T1R3, but not in the mouseversion. Next, we explored the effects of gymnemic acids inthe human, mouse, and chimeric models and the resultssuggested that the transmembrane domain in human T1R3is essential to gymnemic acid sensitivity. It was alsodeduced from molecular modeling that gymnemic acidsbind to this site. Furthermore, analysis of the pointmutation of amino acids in the human T1R3transmembrane domain strongly suggested the possibilitythat gymnemic acids bind to the domain surrounded byhelices 3, 5, and 6, and it became clear that theglucuronosyl group of gymnemic acids is important insuppressing sweetness*1.BackgroundHumans perceive sweetness when consuming sugar, whichis a source of energy. Sensitivity to sweetness begins withthe stimulation of sweet taste cells, which are found in thetaste buds on the tongue. We have already demonstratedthat the sweetness sensing and transfer mechanism is anenergy sensor. For example, the obesity-suppressinghormone leptin and the appetite-stimulating hormonescalled endocannabinoids cause sensitivity to sweetness tochange according to the amount of energy in the body*2-4.Sensitivity to sweetness is also affected by temperature: thesweetness response increases as temperatures becomewarmer*5. Furthermore, we demonstrated that there aresweetness transfer pathways other than the sweet tastereceptor subunit T1R3*6.The T1R2/T1R3 sweet taste receptors are G protein-coupledreceptors and the two subunits are known to work togetherto sense sweet substances with various structures.Clarifying the binding properties between sweet tastereceptors and ligands is a matter of urgency, so we soughtto unravel the hitherto-unknown mechanism via whichgymnemic acids suppress sweetness.New achievementWe succeeded in identifying the binding propertiesbetween sweetness-suppressing substances and sweet tastereceptors. In particular, we identified an amino acid residuethat plays a key role when sweet taste receptors aresuppressed, and explained which structures insweetness-suppressing substances are involved insuppressing sweet tastes.Future ProspectsWe have previously discovered that the sweet tastereceptors T1R2/T1R3 are located not only in the oralcavity, but also in a variety of organs throughout the body,and have demonstrated that they are related to a variety offunctions, including sugar absorption in the intestinal tractand insulin secretion in the pancreas. As such, they areinvolved in maintaining homeostasis as energy sensors.The breakdown of homeostasis could potentially lead tolifestyle-related diseases, so the results of this study areUnraveling the Functions of Receptors as Energy Sensors GHighlight of Recent Research