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Comparative Study
.2004 Nov 10;24(45):10260-5.
doi: 10.1523/JNEUROSCI.1225-04.2004.

Bitter taste receptors for saccharin and acesulfame K

Affiliations
Comparative Study

Bitter taste receptors for saccharin and acesulfame K

Christina Kuhn et al. J Neurosci..

Abstract

Weight-conscious subjects and diabetics use the sulfonyl amide sweeteners saccharin and acesulfame K to reduce their calorie and sugar intake. However, the intrinsic bitter aftertaste, which is caused by unknown mechanisms, limits the use of these sweeteners. Here, we show by functional expression experiments in human embryonic kidney cells that saccharin and acesulfame K activate two members of the human TAS2R family (hTAS2R43 and hTAS2R44) at concentrations known to stimulate bitter taste. These receptors are expressed in tongue taste papillae. Moreover, the sweet inhibitor lactisole did not block the responses of cells transfected with TAS2R43 and TAS2R44, whereas it did block the response of cells expressing the sweet taste receptor heteromer hTAS1R2-hTAS1R3. The two receptors were also activated by nanomolar concentrations of aristolochic acid, a purely bitter-tasting compound. Thus, hTAS2R43 and hTAS2R44 function as cognate bitter taste receptors and do not contribute to the sweet taste of saccharin and acesulfame K. Consistent with the in vitro data, cross-adaptation studies in human subjects also support the existence of common receptors for both sulfonyl amide sweeteners.

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Figures

Figure 1.
Figure 1.
Structures of the compounds used. Aristolochic acid preparations consist of two compounds, one of which is devoid of the methoxy group.
Figure 2.
Figure 2.
Functional expression of hTAS2R43 and hTAS2R44. Responses of cells expressing hTAS2R43 (a) or hTAS2R44 (b) or of mock-transfected cells (c) to bath application of 10 μm aristolochic acid, 10 mm saccharin, or 10 mm acesulfame K were recorded in the FLIPR. Cells were seeded in 96-well microtiter plates and loaded with Fluo4-AM (Molecular Probes). Calcium traces were recorded at an excitation wavelength of 488 nm and an emission wavelength of 515 nm. Arrows indicate agonist application. Data of a typical experiment were corrected for and normalized to background fluorescence. Calibration: horizontal bar, 100 sec; vertical bar, ΔF/F = 0.1.
Figure 3.
Figure 3.
Properties of hTAS2R43 and hTAS2R44 in transfected cells. Dose-response relationships of the effects of aristolochic acid (circles), saccharin (squares), and acesulfame K (triangles) on [Ca2+]i in cells expressing hTAS2R43 (a) or hTAS2R44 (b). Cells were seeded in 96-well microtiter plates and loaded with Fluo4-AM. Calcium traces were recorded in the FLIPR as described in Figure 2 before and after stimulation of the cells with various agonist concentrations. Data of at least three independent experiments performed in quadruplicate were processed in SigmaPlot. Data were corrected for and normalized to background fluorescence, and baseline noise was subtracted.
Figure 4.
Figure 4.
Effects of lactisole on cells expressing bitter or sweet taste receptors. Calcium traces of cells transfected with cDNAs for hTAS2R43 (a), hTAS2R44 (b), or the sweet taste receptor subunits hTAS1R2 and hTAS1R3 (c) were recorded as described in Figure 2. Cells were stimulated with 10 mm saccharin in the absence (-) or presence (+) of 0.5 mm lactisole. Arrows indicate bath application of saccharin or of the mixture of saccharin and lactisole. Data of a typical experiment were corrected for and normalized to background fluorescence. Calibration: horizontal bar, 100 sec; vertical bar, ΔF/F = 0.1.
Figure 5.
Figure 5.
Responses of hTAS2R43- and hTAS2R44-expressing cells to various taste compounds. Calcium responses of cells expressing hTAS2R43 (a) and hTAS2R44 (b) that have been challenged with vehicle (control), sucrose (75 mm),d-tryptophan (10 mm), glycine (75 mm), Na-cyclamate (10 mm), Na-saccharin (10 mm), acesulfame K (10 mm), a mixture of Na-glutamate (10 mm) and inosine monophosphate (1 mm) (glutamate + IMP), salicin (10 mm), propylthiouracil (PROP) (0.25 mm), or aristolochic acid Na-salt (0.01 mm). Data of three independent experiments performed in quadruplicate were processed in SigmaPlot. Data were corrected for and normalized to background fluorescence.
Figure 6.
Figure 6.
Adaptation and cross-adaptation of psychophysical responses elicited by the sulfonyl amides and aristolochic acid. In the beginning of the experiment, the subjects rated the bitterness of all four solutions after 15 sec. Then, they took up the primary bitter solution for prolonged times and rated its bitterness at the indicated times. After the panelists spat off the primary bitter solution, they sequentially tasted the other three test solutions and rated their bitter intensity after 15 sec. To assess reversibility, the subjects sequentially rated 30 min later the bitterness of all four test solutions after 15 sec.a, Adaptation to the bitterness of salicin used as a control compound and lack of cross-adaptation with responses to saccharin, acesulfame K, and aristolochic acid.b, Adaptation to the bitter response of aristolochic acid and cross-adaptation with those of both sulfonyl amide sweeteners. Note that the response to salicin was not affected.c, Adaptation to the bitter taste of saccharin and cross-adaptation with those of acesulfame K and aristolochic acid.d, Adaptation to the bitter taste of acesulfame K and cross-adaptation with those of saccharin and aristolochic acid. AA, aristolochic acid; Ace K, acesulfame K; Sac, saccharin; Sal, salicin.
Figure 7.
Figure 7.
In situ hybridization of hTAS2R43 and hTAS2R44 mRNAs in human circumvallate papillae. Twenty micrometer cryostat cross sections of human circumvallate papillae were hybridized with digoxigenin-labeled antisense (a, b) or sense (c, d) riboprobes. After hybridization, sections were treated with RNase A and subjected to high-stringency washes. Probes were detected by using an anti-digoxigenin antibody and colorimetry. Taste buds are circled. Note that both receptor mRNAs were detected in a subset of cells of the majority of taste buds. Scale bar, 50 μm.
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