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. 2024 Apr 25;72(18):10531–10536. doi: 10.1021/acs.jafc.3c08775

Influence of Sodium Chloride on Human Bitter Taste Receptor Responses

Praveen Kumar 1, Maik Behrens 1,*
PMCID: PMC11082923  PMID: 38663860

Abstract

graphic file with name jf3c08775_0005.jpg

In the past, taste interactions between sodium chloride (NaCl) and bitter tastants were investigated in human sensory studies, and the suppression of bitterness by sodium was observed. It is currently not clear if this phenomenon occurs predominantly peripherally or centrally and if the effect is general or only particular bitter compounds are blocked. Therefore, the influence of NaCl at the receptor level was tested by functional expression assays using four out of ∼25 human bitter taste receptors together with prototypical agonists. It was observed that NaCl affected only the responses of particular bitter taste receptor-compound pairs, whereas other bitter responses remained unchanged upon variations of the sodium concentrations. Among the tested receptors, TAS2R16 showed a reduction in signaling in the presence of NaCl. This demonstrates that for some receptor-agonist pairs, NaCl reduces the activation at the receptor level, whereas central effects may dominate the NaCl-induced bitter taste inhibition for other substances.

Keywords: G protein-coupled receptors, bitter suppression, calcium mobilization assay, TAS2R16, salicin, N-methyl-d-glucamine, sodium chloride

1. Introduction

In vertebrates, dietary nutrients are sensed in the oral cavity through the taste system, which has evolved to distinguish between nutrients and potentially harmful food components.1 In general, vertebrate taste systems are equipped with receptors that detect sweet, salty, umami (savory taste of primarily l-Glu in humans), sour, and bitter tasting substances.2 Salty and sour tastes are mediated by the ion channel ENaC3 and otopetrin-1,4−6 respectively. Bitter, sweet, and umami tastes are mediated by G protein-coupled receptors (GPCRs) of the taste 1 receptor and taste 2 receptor families.7 NaCl elicits salty taste, and subthreshold concentrations of NaCl were reported to reduce the bitterness of caffeine.8 This study was also supported by human sensory studies, where each taste attribute is typically perceived as being less intense in two-component mixtures than when they are tasted separately.9−11 Breslin and Beauchamp12 and Keast13 performed sensory experiments with several salty and bitter compounds and demonstrated the suppression of bitterness of an array of compounds by addition of sodium salts. However, whether the underlying mechanism for this phenomenon involves mainly peripheral components such as bitter taste receptors or central processing remained unknown.

Previous studies suggest that humans are equipped with about 25 bitter taste receptor genes14−17 that are expressed in a heterogeneous pattern in taste buds of the oral cavity18 to detect hundreds of structurally diverse bitter compounds.19 Their agonist selectivities have shown to be considerably different.17 TAS2R16 and TAS2R38 are highly selective for βd-glucopyranosides and isothiocyanates/thioureas, respectively.20,21 Besides that, TAS2R10,21,22 TAS2R14,23,24 and TAS2R4625,26 are broadly tuned receptors that can recognize a large number of chemically distinct bitter substances.17 Studies on in vitro expressed human bitter taste receptors demonstrated the suppression of TAS2R16 signaling by umami substances such as monosodium glutamate.27

In order to investigate a possible bitter suppression by sodium chloride at the receptor level, a functional screening approach using the cDNAs of TAS2R14, TAS2R16, TAS2R43, and TAS2R46 receptors expressed in a mammalian cell line was employed. Receptors whose activity was suppressed by increasing the sodium salt were further characterized.

2. Materials and Methods

2.1. Chemicals

N-methyl-d-glucamine, Sodium gluconate, d-salicin, phenyl-βd-glucopyranoside, Flufenamic acid, Aristolochic acid 1 (Sodium salt), and Strychnine hemisulfate salt were purchased from Sigma-Aldrich. Gentiobiose was acquired from Carl Roth, Karlsruhe, and the source of Helicin was Tokyo Chemical Industry.

2.2. Functional Screening of Bitter Compounds

The functional screening experiments were performed in accordance with earlier publications.28−30 HEK 293T-Gα16gust44 cells were grown in poly-d-lysine-coated 96 well plates under standard conditions (DMEM, 10% FCS, 1% penicillin/streptomycin, 1% glutamine; 37°C, 5% CO2, 95% humidity), and lipofectamine 2000 (Thermo Fisher Scientific, Darmstadt, Germany) was used to transiently transfect cells with TAS2R cDNA constructs. Empty vector (mock) was used to transfect cells as a negative control. On the next day (about 24 h after transfection), cells were stained with calcium-sensitive dye Fluo4-AM (Thermo Fisher Scientific, Darmstadt, Germany) for 1 h in the presence of probenecid (2.5 mM, Sigma-Aldrich, Steinheim, Germany). Before the start of the measurements, cells were washed two times with C1 buffer (130 mM NaCl, 10 mM HEPES, 5 mM KCl, 2 mM CaCl2, 0.18% glucose; pH 7.4), and a fluorometric imaging plate reader (FLIPRTetra, Molecular Devices, San Jose, CA) was used to monitor the fluorescence changes. Fluo4-AM in the loaded cells was excited with 488 nm of light after automated application of the bitter substances, and emission was recorded at 510 nm. To ensure cell viability, somatostatin 14 (100 nM, Bachem, Bubendorf, Switzerland) was subsequently applied to the cells at the end of each experiment.

2.3. Recording and Calculations

For the initial screening of candidate compound-receptor pairs, three different concentrations of bitter agonists were applied to cells expressing the individual receptors. Taking into account both substance solubilities and receptor dependence of compound-induced fluorescence changes, the highest concentrations were chosen based on earlier experiments.17,31,32 Different concentrations of NaCl were used in C1 buffer preparations by replacing it with N-methyl-d-glucamine or sodium gluconate.33 First C1 buffer contained 0 mM NaCl, which was substituted with equimolar (130 mM) NMDG.33 Second C1 buffer contained 65 mM NaCl and 65 mM NMDG, whereas the third contained 130 mM NaCl, which is the standard salt concentration used in functional assays. The bitter compounds were diluted in the same C1 buffer solution, and at least duplicate wells for each compound concentration-receptor combinations were measured. To determine if the inhibition by sodium is concentration dependent, TAS2R16 responses in the presence of 10, 1, and 0.1 mM salicin were monitored. These salicin mixtures were prepared in buffers which contained different sodium chloride concentrations (0, 22, 43, 65, 87, 108, and 130 mM). In order to establish dose–response relationships of TAS2R16 with d-salicin, phenyl-βd-glucopyranoside, helicin,21 and gentiobiose,34 cells were seeded, transfected, and stimulated as described for the screening procedure. Compound-specific changes in fluorescence (ΔF/F) were computed by subtracting and normalizing data from identically treated mock controls according to the background fluorescence. The half-maximal effective concentration (EC50) was calculated and plotted by using SigmaPlot 14 software as previously published.28,35

2.4. Statistics

The lowest concentration at which bitter receptor responses were noticeably larger than the control was referred to as the threshold concentration. Data were collected from at least three independent experiments. Data are presented as means ± the standard error of the mean (SEM). Student’s t-test was applied to observe statistical significance, and p < 0.05 is considered as significant difference.

3. Results and Discussion

3.1. Sodium Salt Demonstrate Receptor Selective Blocking Activities

To test if sodium salts demonstrate receptor-specific or rather general bitter-blocking activities, experiments with three different C1 buffers containing different sodium salt combinations were performed. Out of 26 human bitter taste receptors, four TAS2Rs that cover a range of different features were selected for functional expression assays. The TAS2R14 is very broadly tuned with numerous chemically diverse agonists;23 the TAS2R46 is also broadly tuned but shows a certain bias toward natural agonists such as sesquiterpene lactones;25 the TAS2R16 is specific for the substance class of βd-glucopyranosides;21 and the TAS2R43 exhibits an intermediate agonist spectrum.17 Their most potent agonists, according to previous studies, with three different concentrations (1:10 dilution) were chosen for functional screening. TAS2R16 activity with salicin21 (10, 1, and 0.1 mM), TAS2R14 activity with flufenamic acid24 (10, 1, and 0.1 μM), TAS2R43 activity with aristolochic acid36 (10, 1, and 0.1 μM), and TAS2R46 activity with strychnine25 (10, 1, and 0.1 μM) were screened and further assessed for the relative fluorescence changes (ΔF/F) induced by the agonists in three different concentrations of sodium salt containing buffers (Figure 1). A significantly higher response in TAS2R16 to 10 mM salicin in the absence of sodium salt was observed, but other receptor responses were largely unchanged. This observation suggests that sodium chloride exerts a receptor-/substance-specific bitter-blocking effect on TAS2R16.

Figure 1.

Figure 1

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Functional screening of TAS2R16, TAS2R14, TAS2R43, and TAS2R46 with their respective agonists in the presence, absence, and with reduced sodium chloride content. Receptors were transiently transfected into HEK 293T-Gα16gust44 cells and screened by calcium imaging. (A) Application of salicin on TAS2R16-transfected HEK 293T-Gα16gust44 cells at the indicated concentrations in the different buffer solutions. (B) Application of flufenamic acid on TAS2R14 transfected HEK 293T-Gα16gust44 cells at the indicated concentrations in the different buffer solutions. (C) Application of aristolochic acid on TAS2R43 transfected HEK 293T-Gα16gust44 cells at the indicated concentrations in the different buffer solutions. (D) Application of strychnine on TAS2R46 transfected HEK 293T-Gα16gust44 cells at the indicated concentrations in the different buffer solutions. The asterisk indicates the significant reduction (p < 0.01) in calcium response of TAS2R16-salicin pair in the presence of NaCl compared to the absence of NaCl. (NMDG: N-Methyl-d-glucamine containing buffer, NMDG + NaCl: combination of N-Methyl-d-glucamine and sodium chloride containing buffer, NaCl: sodium chloride containing buffer).

3.2. Sodium Salt Suppresses d-Salicin Activation of TAS2R16

To find out if the sodium salt inhibition of TAS2R16 responses to salicin is agonist selective, TAS2R16 expression at the cell surface of HEK 293T-Gα16gust44 cells was confirmed (see supporting data; Figure S1), and the salicin responsiveness of TAS2R16 was investigated in more detail. Full dose–response relationships in the presence and absence of sodium salt were determined and compared (Figure 2). Salicin in both buffers activated TAS2R16 at a threshold concentration of ∼0.3 mM, and the saturation of the receptor responses allowed us to determine the half-maximal activating concentration (EC50) (Figure 2A). An EC50-concentration of 2.37 ± 0.63 mM in the absence of NaCl was determined, whereas in the presence of NaCl, it was 1.28 ± 0.18 mM. The maximum response of 30 mM salicin in the absence of sodium salt was increased, on average, by 25%. To exclude that the sodium chloride reduction of TAS2R16 signaling was mediated by the chloride anion instead of the sodium cation, sodium gluconate was tested as well. No significant differences between NaCl and Na gluconate were observed attesting to the critical role of sodium ions. In order to find out whether the different sodium concentrations affect the receptor, the agonist, or both components, full dose–response relationships for phenyl-βd-glucopyranoside, helicin, gentiobiose, and other cognate agonists of TAS2R1621,34 were monitored (Figure 2). Similar to salicin, signal saturation of TAS2R16 was achieved with phenyl-βd-glucopyranoside and helicin, allowing the determination of EC50-concentrations (Figure 2B,C). However, due to substantial receptor-independent artifacts at gentiobiose concentrations above 10 mM, an EC50-concentration could not be determined (Figure 2D). Whereas phenyl-βd-glucopyranoside and gentiobiose activation of TAS2R16 appear unaffected by sodium chloride. Helicin responses in the absence of sodium chloride are significantly increased at concentrations of 1 and 3 mM and, consequently, a shift in the dose–response relationship was observed (Figure 2C). This increase in the slope in the absence of sodium ions suggests negative cooperativity, which may hint at a negative allosteric effect exerted by sodium ions. Hence, both agonists carrying an oxygen atom in the aglycon moiety show impaired signaling at TAS2R16 in the presence of sodium ions. For salicin, this is further substantiated by the comparison of the raw fluorescence traces of TAS2R16 expressing cells in the absence and presence of sodium depicted in Figure 3. Here, the peak response of TAS2R16 is clearly lower in the presence of sodium salt, whereas the downhill slopes are similar.

Figure 2.

Figure 2

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Effect of buffer ions on the agonist-dependent activation of TAS2R16. (A) Using transiently transfected HEK 293T-Gα16gust44 cells expressing the TAS2R16 construct, the dose–response relationship of salicin was established in the presence (red curve) and absence of NaCl (black curve) in the buffer. To exclude that the sodium chloride reduction of TAS2R16 signaling was mediated by the chloride anion instead of the sodium cation, sodium gluconate (blue curve) was tested as well. (B) Dose–response relationship of TAS2R16 stimulated with phenyl-βd-glucopyranoside in the presence and absence of sodium salt in the buffer. (C) Dose–response relationship of TAS2R16 stimulated with helicin in the presence and absence of sodium salt in the buffer. (D) Dose–response relationship of TAS2R16 stimulated with gentiobiose in the presence and absence of sodium salt in the buffer. In the four panels, the logarithm of the agonist concentrations applied to the cells is displayed on the x-axis, and the relative changes in fluorescence (ΔF/F) are plotted on the y-axis. Structural formulas of the employed agonists were placed in the corresponding graphs. A fluorometric imaging plate reader (FLIPRtetra) was used for fluorescence measurements and automated agonist applications. The lowest test concentration that results in statistically significant fluorescence changes (Student’s t test, p < 0.05) in comparison to mock controls is considered as threshold concentration. EC50-concentrations were calculated with the SigmaPlot program. Emax = maximum signal amplitudes. Every measurement was carried out at least four times with two technical replicates for each concentration. The asterisks indicate significant differences in calcium responses in the presence and absence of NaCl. The 30 mM salicin-TAS2R16 signal response increased in the absence of NaCl by 25%. (NMDG: N-Methyl-d-glucamine containing buffer, NaCl: sodium chloride containing buffer, Na gluconate: sodium gluconate containing buffer).

Figure 3.

Figure 3

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Exemplary fluorescence traces of TAS2R16 expressing cells stimulated with 30 mM salicin in the presence of 130 mM NaCl and in the absence of NaCl (130 mM NMDG). The TAS2R16 expression construct was transiently transfected in HEK 293T-Gα16gust44 cells and stimulated with 30 mM salicin. The fluorescence traces of salicin eliciting responses in different C1 media are overlaid, demonstrating a reduction in the calcium response by 39% in the presence of sodium chloride. Empty vector transfected and identically treated cells were used as negative controls (not shown). (NMDG: N-Methyl-d-glucamine containing buffer, NaCl: sodium chloride containing buffer.) Scale bar (right side); 2500 relative fluorescence units, 200 s.

3.3. Concentration Dependence of Sodium Salt Inhibition of d-Salicin-TAS2R16 Signaling

To further investigate if the extent of sodium inhibition is concentration dependent, calcium assay experiments were performed and TAS2R16 responses in the presence of 10, 1, and 0.1 mM salicin were monitored (Figure 4). The inhibitory effect of sodium salt on TAS2R16-salicin response indicates a considerable and dose-dependent reduction between 0 mM and 43 mM NaCl.

Figure 4.

Figure 4

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Inhibition curve of TAS2R16-salicin responsiveness with a sodium salt. Receptors were transiently transfected in HEK 293T-Gα16gust44 cells and screened by calcium imaging. Application of salicin on TAS2R16-transfected HEK 293T-Gα16gust44 cells at the indicated concentrations in the different buffer solutions was investigated. Salicin was dissolved in the different buffer solutions containing NaCl (final concentrations = 0, 22, 43, 65, 87, 108, and 130 mM). Asterisks indicate significant reduction of calcium responses in the presence of NaCl compared to the absence of NaCl (p < 0.05).

These results indicate that the effect of sodium salt to suppress TAS2R16 activation by salicin is directly correlated with sodium salt concentrations. It remains to be determined whether the observed inhibition is caused by the interaction of sodium with salicin, the receptor, or subtle changes in the solution properties of the buffering system. Taking into account previous in vivo studies related to two-component bitter-salty mixtures,12,13 we speculate that our results hint at a dominant effect caused by centrally mediated mixture-suppression with individual contributions of receptor-agonist combinations, as our data suggest that sodium salt does not seem to have general function on bitter taste receptors. Evidence has emerged from previous calcium imaging analyses of HEK 293T cells expressing TAS2R16 indicating that TAS2R16 response to salicin was also reduced in the presence of acidic dipeptides and the inhibition was pH values dependent.37 This may hint at a function of positive ions, such as protons or sodium ions, being involved in the modulation of TAS2R16 responses with select agonists. Taken together, it was confirmed that sodium chloride inhibition of bitter taste responses is not caused by a single mechanism but rather involves peripheral as well as central processing steps.

Acknowledgments

The authors thank Catherine Delaporte for excellent technical assistance.

Glossary

Abbreviations and Nomenclatures

HEK293T

human embryonic kidney cells 293 transferase

NaCl

sodium chloride

NMDG

N-methyl-d-glucamine

TAS2R

taste 2 receptor

EC50

half-maximum effective concentration

mM

milliMolar

μM

microMolar

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jafc.3c08775.

  • Immunocytochemical staining of the human bitter taste receptor TAS2R16 expressed in HEK 293T-Gα16gust44 cells: Experimental procedure and results (Figure S1) (PDF)

The authors declare no competing financial interest.

Special Issue

Published as part of Journal of Agricultural and Food Chemistryvirtual special issue “13th Wartburg Symposium on Flavor Chemistry and Biology.”

Supplementary Material

jf3c08775_si_001.pdf (207.9KB, pdf)

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Supplementary Materials

jf3c08775_si_001.pdf (207.9KB, pdf)

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