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PNAS 101 (39): 14258-14263

Copyright © 2004 by the National Academy of Sciences.

From the Cover

NEUROSCIENCE

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: xiaodong.li{at}senomyx.com.

© 2004 by The National Academy of Sciences of the USA

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