Journal of Biological Chemistry
Volume 280, Issue 15, 15 April 2005, Pages 15238-15246
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Mechanisms of Signal Transduction
Lactisole Interacts with the Transmembrane Domains of Human T1R3 to Inhibit Sweet Taste*

https://doi.org/10.1074/jbc.M414287200Get rights and content
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The detection of sweet-tasting compounds is mediated in large part by a heterodimeric receptor comprised of T1R2+T1R3. Lactisole, a broad-acting sweet antagonist, suppresses the sweet taste of sugars, protein sweeteners, and artificial sweeteners. Lactisole's inhibitory effect is specific to humans and other primates; lactisole does not affect responses to sweet compounds in rodents. By heterologously expressing interspecies combinations of T1R2+T1R3, we have determined that the target for lactisole's action is human T1R3. From studies with mouse/human chimeras of T1R3, we determined that the molecular basis for sensitivity to lactisole depends on only a few residues within the transmembrane region of human T1R3. Alanine substitution of residues in the transmembrane region of human T1R3 revealed 4 key residues required for sensitivity to lactisole. In our model of T1R3's seven transmembrane helices, lactisole is predicted to dock to a binding pocket within the transmembrane region that includes these 4 key residues.

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*

This work was supported in part by National Institute of Health Grants 1 F32 DC007021-01 (to P. J.), DC003055 and DC003155 (to R. F. M), and MH58811 (to M. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains four supplementary figures.

An Associate Investigator of Howard Hughes Medical Institute.