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Advanced Glycation End-Products Can Activate or Block Bitter Taste Receptors.

ABSTRACT: Bitter taste receptors (T2Rs) are expressed in several tissues of the body and are involved in a variety of roles apart from bitter taste perception. Advanced glycation end-products (AGEs) are produced by glycation of amino acids in proteins. There are varying sources of AGEs, including dietary food products, as well as endogenous reactions within our body. Whether these AGEs are T2R ligands remains to be characterized. In this study, we selected two AGEs, namely, glyoxal-derived lysine dimer (GOLD) and carboxymethyllysine (CML), based on their predicted interaction with the well-studied T2R4, and its physiochemical properties. Results showed predicted binding affinities (Kd) for GOLD and CML towards T2R4 in the nM and ?M range, respectively. Calcium mobilization assays showed that GOLD inhibited quinine activation of T2R4 with IC50 10.52 ± 4.7 ?M, whilst CML was less effective with IC50 32.62 ± 9.5 ?M. To characterize whether this antagonism was specific to quinine activated T2R4 or applicable to other T2Rs, we selected T2R14 and T2R20, which are expressed at significant levels in different human tissues. A similar effect of GOLD was observed with T2R14; and in contrast, GOLD and CML activated T2R20 with an EC50 of 79.35 ± 29.16 ?M and 65.31 ± 17.79 ?M, respectively. In this study, we identified AGEs as novel T2R ligands that caused either activation or inhibition of different T2Rs.

SUBMITTER: Jaggupilli A

PROVIDER: S-EPMC6628017 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Advanced Glycation End-Products Can Activate or Block Bitter Taste Receptors.

Jaggupilli Appalaraju A Howard Ryan R Aluko Rotimi E RE Chelikani Prashen P

Nutrients 20190612 6

Bitter taste receptors (T2Rs) are expressed in several tissues of the body and are involved in a variety of roles apart from bitter taste perception. Advanced glycation end-products (AGEs) are produced by glycation of amino acids in proteins. There are varying sources of AGEs, including dietary food products, as well as endogenous reactions within our body. Whether these AGEs are T2R ligands remains to be characterized. In this study, we selected two AGEs, namely, glyoxal-derived lysine dimer (G ...[more]

PMID: 31212814

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Project description:ImportanceAdvanced glycation end products (AGEs) and their receptor (RAGE) are implicated in the pathophysiological processes of dementia and potentially underlie the association of diabetes with neurodegeneration. However, longitudinal studies examining this association are lacking.ObjectiveTo determine whether markers of the AGE-RAGE system are associated with prevalent and incident dementia and with cognition.Design, setting, and participantsIn this population-based cohort study including participants from the prospective Rotterdam Study, extracellular newly identified RAGE binding protein (EN-RAGE) and soluble RAGE (S-RAGE) were measured in plasma collected between 1997 and 1999 in a random selection of participants, and additionally in participants with prevalent dementia. Participants without dementia were followed up for dementia until 2016. Skin AGEs, measured as skin autofluorescence, and cognition were measured between 2013 and 2016 in participants without dementia. Data analysis was performed from June 2019 to December 2019.ExposuresEN-RAGE, S-RAGE, and skin autofluorescence.Main outcomes and measuresPrevalent and incident dementia and cognition, adjusted for potential confounders, including age, sex, diabetes, educational level, APOE ε4 carrier status, smoking, and estimated glomerular filtration rate.ResultsOf 3889 included participants (mean [SD] age, 72.5 [8.9] years; 2187 [56.2%] women), 1021 participants had data on plasma markers (mean [SD] age 73.6 [7.8] years; 564 [55.2%] women), 73 participants had dementia at baseline, and during 10 711 person-years of follow-up, 161 participants developed incident dementia. Compared with low levels, high EN-RAGE level was associated with a higher prevalence of dementia (odds ratio [OR], 3.68 [95% CI, 1.50-8.03]; P = .003), while high S-RAGE level was associated with a lower prevalence of dementia (OR, 0.37 [95% CI, 0.17-0.78]; P = .01). These associations attenuated in a longitudinal setting, with hazard ratios of 0.65 (95% CI, 0.42-1.01) for high EN-RAGE (P = .05) and 1.22 (95% CI, 0.82-1.81) for high S-RAGE (P = .33). Among 2890 participants without dementia (mean [SD] age, 72.5 [9.4] years; 1640 [57%] women), higher skin autofluorescence was associated with lower global cognitive function (adjusted difference in z score per 1-SD higher skin autofluorescence, -0.07 [95% CI, -0.11 to -0.04]), especially among carriers of the APOE ε4 allele (adjusted difference in z score per 1-SD higher skin autofluorescence, -0.15 [95% CI, -0.22 to -0.07]).Conclusions and relevanceThese findings suggest that the AGE-RAGE system is associated with cognitive decline and dementia cross-sectionally but not longitudinally. This indicates either a short-term association or reverse causality. Findings of cross-sectional associations between higher skin autofluorescence and lower cognitive function and an association with APOE status also warrant replication and prospective studies.

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Advanced Glycation End-Products Can Activate or Block Bitter Taste Receptors.

Publications

Advanced Glycation End-Products Can Activate or Block Bitter Taste Receptors.

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