title: Different functional roles of T1R subunits in the heteromeric taste receptors.
abstract: The T1R receptors, a family of taste-specific class C G protein-coupled receptors, mediate mammalian sweet and umami tastes. The structure-function relationships of T1R receptors remain largely unknown. In this study, we demonstrate the different functional roles of T1R extracellular and transmembrane domains in ligand recognition and G protein coupling. Similar to other family C G protein-coupled receptors, the N-terminal Venus flytrap domain of T1R2 is required for recognizing sweeteners, such as aspartame and neotame. The G protein coupling requires the transmembrane domain of T1R2. Surprisingly, the C-terminal transmembrane domain of T1R3 is required for recognizing sweetener cyclamate and sweet taste inhibitor lactisole. Because T1R3 is the common subunit in the sweet taste receptor and the umami taste receptor, we tested the interaction of lactisole and cyclamate with the umami taste receptor. Lactisole inhibits the activity of the human T1R1/T1R3 receptor, and, as predicted, blocked the umami taste of l-glutamate in human taste tests. Cyclamate does not activate the T1R1/T1R3 receptor by itself, but potentiates the receptor's response to l-glutamate. Taken together, these findings demonstrate the different functional roles of T1R3 and T1R2 and the presence of multiple ligand binding sites on the sweet taste receptor.
authors.affiliation: Senomyx, Inc., 11099 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.forename: Lena
authors.initials: L
authors.lastname: Staszewski
authors.forename: Huixian
authors.initials: H
authors.lastname: Tang
authors.forename: Elliot
authors.initials: E
authors.lastname: Adler
authors.forename: Mark
authors.initials: M
authors.lastname: Zoller
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001218:Aspartame / Q000494:pharmacology; D001555:Benzene Derivatives / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D003494:Cyclamates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005421:Flavoring Agents / Q000494:pharmacology; D005971:Glutamates / Q000494:pharmacology; D020962:Heterotrimeric GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000502:physiology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D012970:Sodium Glutamate / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013395:Sucrose / Q000494:pharmacology; D013649:Taste / Q000187:drug effects / Q000502:physiology; D013650:Taste Buds / Q000502:physiology*; D014162:Transfection
chemical_list: D001555:Benzene Derivatives; D003494:Cyclamates; D005421:Flavoring Agents; D005971:Glutamates; D021122:Protein Subunits; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; C431926:taste receptors, type 1; D013395:Sucrose; D020962:Heterotrimeric GTP-Binding Proteins; D012970:Sodium Glutamate; D001218:Aspartame; C495512:lactisole