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PNAS 101 (39): 14258-14263

Copyright © 2004 by the National Academy of Sciences.

From the Cover


Different functional roles of T1R subunits in the heteromeric taste receptors

Hong Xu, Lena Staszewski *, Huixian Tang, Elliot Adler {dagger}, Mark Zoller, and Xiaodong Li {ddagger}

Senomyx, Inc., 11099 North Torrey Pines Road, La Jolla, CA 92037

Edited by Solomon H. Snyder, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved August 9, 2004

Received for publication June 18, 2004.

Abstract: The T1R receptors, a family of taste-specific class C G proteincoupled 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.

This paper was submitted directly (Track II) to the PNAS office.

Freely available online through the PNAS open access option.

Abbreviations: GPCR, G protein-coupled receptor; HEK, human embryonic kidney; mGluR, metabotropic glutamate receptor; GABABR, {gamma}-aminobutyric acid type B receptor; FLIPR, fluorescence imaging plate reader; AceK, acesulfame K.

See Commentary on page 13972.

* Present address: Kalypsys, Inc., 10420 Wateridge Circle, San Diego, CA 92121.

{dagger} Present address: Harvard Law School, 1563 Massachusetts Avenue, Cambridge, MA 02138.

{ddagger} To whom correspondence should be addressed. E-mail:{at}

© 2004 by The National Academy of Sciences of the USA

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
Human sweet taste receptor mediates acid-induced sweetness of miraculin.
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   Abstract »    Full Text »    PDF »
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J. Neurosci. 31, 13527-13534
   Abstract »    Full Text »    PDF »
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B. Liu, M. Ha, X.-Y. Meng, T. Kaur, M. Khaleduzzaman, Z. Zhang, P. Jiang, X. Li, and M. Cui (2011)
J. Neurosci. 31, 11070-11076
   Abstract »    Full Text »    PDF »
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Chem Senses 36, 527-537
   Abstract »    Full Text »    PDF »
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X. Li, A. A. Bachmanov, K. Maehashi, W. Li, R. Lim, J. G. Brand, G. K. Beauchamp, D. R. Reed, C. Thai, and W. B. Floriano (2011)
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   Abstract »    Full Text »    PDF »
Reduced Sweetness of a Monellin (MNEI) Mutant Results from Increased Protein Flexibility and Disruption of a Distant Poly-(L-Proline) II Helix.
C. M. Templeton, S. Ostovar pour, J. R. Hobbs, E. W. Blanch, S. D. Munger, and G. L. Conn (2011)
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   Abstract »    Full Text »    PDF »
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K. K. Yee, S. K. Sukumaran, R. Kotha, T. A. Gilbertson, and R. F. Margolskee (2011)
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   Abstract »    Full Text »    PDF »
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J. Biol. Chem. 286, 9985-9997
   Abstract »    Full Text »    PDF »
Temporal coding of odor mixtures in an olfactory receptor neuron.
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
SuperSweet--a resource on natural and artificial sweetening agents.
J. Ahmed, S. Preissner, M. Dunkel, C. L. Worth, A. Eckert, and R. Preissner (2011)
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   Abstract »    Full Text »    PDF »
Allostery at G Protein-Coupled Receptor Homo- and Heteromers: Uncharted Pharmacological Landscapes.
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   Abstract »    Full Text »    PDF »
Genetic variation in TAS1R2 (Ile191Val) is associated with consumption of sugars in overweight and obese individuals in 2 distinct populations.
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J. Biol. Chem. 285, 28373-28378
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
Variation in umami perception and in candidate genes for the umami receptor in mice and humans.
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   Abstract »    Full Text »    PDF »
Perceptual variation in umami taste and polymorphisms in TAS1R taste receptor genes.
Q.-Y. Chen, S. Alarcon, A. Tharp, O. M Ahmed, N. L Estrella, T. A Greene, J. Rucker, and P. A. Breslin (2009)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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X. Li, D. Glaser, W. Li, W. E. Johnson, S. J. O'Brien, G. K. Beauchamp, and J. G. Brand (2009)
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   Abstract »    Full Text »    PDF »
T1R2 and T1R3 subunits are individually unnecessary for normal affective licking responses to polycose: implications for saccharide taste receptors in mice.
Y. Treesukosol, G. D. Blonde, and A. C. Spector (2009)
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   Abstract »    Full Text »    PDF »
Incretin release from gut is acutely enhanced by sugar but not by sweeteners in vivo.
Y. Fujita, R. D. Wideman, M. Speck, A. Asadi, D. S. King, T. D. Webber, M. Haneda, and T. J. Kieffer (2009)
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   Abstract »    Full Text »    PDF »
Molecular mechanism for the umami taste synergism.
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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J. Endocrinol. 196, 435-453
   Abstract »    Full Text »    PDF »
Allelic variation of the Tas1r3 taste receptor gene selectively affects taste responses to sweeteners: evidence from 129.B6-Tas1r3 congenic mice.
M. Inoue, J. I. Glendinning, M. L. Theodorides, S. Harkness, X. Li, N. Bosak, G. K. Beauchamp, and A. A. Bachmanov (2007)
Physiol Genomics 32, 82-94
   Abstract »    Full Text »    PDF »
A Drosophila gustatory receptor required for the responses to sucrose, glucose, and maltose identified by mRNA tagging.
Y. Jiao, S. J. Moon, and C. Montell (2007)
PNAS 104, 14110-14115
   Abstract »    Full Text »    PDF »
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J.-P. Pin, R. Neubig, M. Bouvier, L. Devi, M. Filizola, J. A. Javitch, M. J. Lohse, G. Milligan, K. Palczewski, M. Parmentier, et al. (2007)
Pharmacol. Rev. 59, 5-13
   Abstract »    Full Text »    PDF »
Asymmetric conformational changes in a GPCR dimer controlled by G-proteins.
M. Damian, A. Martin, D. Mesnier, J.-P. Pin, and J.-L. Baneres (2006)
EMBO J. 25, 5693-5702
   Abstract »    Full Text »    PDF »
Do orphan G-protein-coupled receptors have ligand-independent functions?: New insights from receptor heterodimers.
A. Levoye, J. Dam, M. A. Ayoub, J.-L. Guillaume, and R. Jockers (2006)
EMBO Rep. 7, 1094-1098
   Abstract »    Full Text »    PDF »
Variation in the Human TAS1R Taste Receptor Genes.
U.-k. Kim, S. Wooding, N. Riaz, L. B. Jorde, and D. Drayna (2006)
Chem Senses 31, 599-611
   Abstract »    Full Text »    PDF »
The orphan GPR50 receptor specifically inhibits MT1 melatonin receptor function through heterodimerization.
A. Levoye, J. Dam, M. A. Ayoub, J.-L. Guillaume, C. Couturier, P. Delagrange, and R. Jockers (2006)
EMBO J. 25, 3012-3023
   Abstract »    Full Text »    PDF »
Expression and Purification of Functional Ligand-Binding Domains of T1R3 Taste Receptors.
Y. Nie, J. R. Hobbs, S. Vigues, W. J. Olson, G. L. Conn, and S. D. Munger (2006)
Chem Senses 31, 505-513
   Abstract »    Full Text »    PDF »
Taste Responses to Sweet Stimuli in {alpha}-Gustducin Knockout and Wild-Type Mice.
V. Danilova, S. Damak, R. F. Margolskee, and G. Hellekant (2006)
Chem Senses 31, 573-580
   Abstract »    Full Text »    PDF »
Extracellular Production of Neoculin, a Sweet-Tasting Heterodimeric Protein with Taste-Modifying Activity, by Aspergillus oryzae.
K.-i. Nakajima, T. Asakura, J.-i. Maruyama, Y. Morita, H. Oike, A. Shimizu-Ibuka, T. Misaka, H. Sorimachi, S. Arai, K. Kitamoto, et al. (2006)
Appl. Envir. Microbiol. 72, 3716-3723
   Abstract »    Full Text »    PDF »
The Liaison of Sweet and Savory.
V. Galindo-Cuspinera and P. A.S. Breslin (2006)
Chem Senses 31, 221-225
   Abstract »    Full Text »    PDF »
Contrasting Modes of Evolution Between Vertebrate Sweet/Umami Receptor Genes and Bitter Receptor Genes.
P. Shi and J. Zhang (2006)
Mol. Biol. Evol. 23, 292-300
   Abstract »    Full Text »    PDF »
Oligomerization of G-Protein-Coupled Receptors: Lessons from the Yeast Saccharomyces cerevisiae.
M. C. Overton, S. L. Chinault, and K. J. Blumer (2005)
Eukaryot. Cell 4, 1963-1970
   Full Text »    PDF »
Delineating a Ca2+ Binding Pocket within the Venus Flytrap Module of the Human Calcium-sensing Receptor.
C. Silve, C. Petrel, C. Leroy, H. Bruel, E. Mallet, D. Rognan, and M. Ruat (2005)
J. Biol. Chem. 280, 37917-37923
   Abstract »    Full Text »    PDF »
Identification of the Cyclamate Interaction Site within the Transmembrane Domain of the Human Sweet Taste Receptor Subunit T1R3.
P. Jiang, M. Cui, B. Zhao, L. A. Snyder, L. M. J. Benard, R. Osman, M. Max, and R. F. Margolskee (2005)
J. Biol. Chem. 280, 34296-34305
   Abstract »    Full Text »    PDF »
Initial Licking Responses of Mice to Sweeteners: Effects of Tas1r3 Polymorphisms.
J. I. Glendinning, S. Chyou, I. Lin, M. Onishi, P. Patel, and K. H. Zheng (2005)
Chem Senses 30, 601-614
   Abstract »    Full Text »    PDF »
Asymmetric Functioning of Dimeric Metabotropic Glutamate Receptors Disclosed by Positive Allosteric Modulators.
C. Goudet, J. Kniazeff, V. Hlavackova, F. Malhaire, D. Maurel, F. Acher, J. Blahos, L. Prezeau, and J.-P. Pin (2005)
J. Biol. Chem. 280, 24380-24385
   Abstract »    Full Text »    PDF »
Sensory Systems: Taste Perception.
R. F. Margolskee (2005)
Sci. STKE 2005, tr20
   Abstract »    Full Text »    PDF »
Lactisole Interacts with the Transmembrane Domains of Human T1R3 to Inhibit Sweet Taste.
P. Jiang, M. Cui, B. Zhao, Z. Liu, L. A. Snyder, L. M. J. Benard, R. Osman, R. F. Margolskee, and M. Max (2005)
J. Biol. Chem. 280, 15238-15246
   Abstract »    Full Text »    PDF »
Evidence for a single heptahelical domain being turned on upon activation of a dimeric GPCR.
V. Hlavackova, C. Goudet, J. Kniazeff, A. Zikova, D. Maurel, C. Vol, J. Trojanova, L. Prezeau, J.-P. Pin, and J. Blahos (2005)
EMBO J. 24, 499-509
   Abstract »    Full Text »    PDF »
Unraveling the biochemistry of sweet and umami tastes.
G. E. DuBois (2004)
PNAS 101, 13972-13973
   Full Text »    PDF »

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