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Psychophysical dissection of genotype effects on human bitter perception.

ABSTRACT: The purpose of this study was to define the effects of individual polymorphisms within the haplotypes of the TAS2R38 taste receptor gene on human bitter taste perception. A racially and ethnically diverse sample of children and adults (N = 980) was phenotyped for thresholds of 6-n-propylthiouracil (PROP) and genotyped for 3 polymorphisms of the TAS2R38 gene (A49P, V262A, I296V). Subjects were grouped according to their diplotype (i.e., specific combinations of haplotypes) and compared for PROP thresholds. By contrasting subjects with particular diplotypes, we found that in addition to A49P, V262A and I296V were related to the ability of the subjects to detect PROP. The V262A variant site affected the ability of subjects to detect mid-range concentrations of PROP, whereas the I296V variant site affected the ability of subjects to perceive PROP at the lowest concentration. These data agree with results from previous studies using cell-based assays for 2 variant sites (A49P and V262A) but not those for the I296V variant site. The reason for the discordant results is not known but it highlights the need for psychophysical as well as cell-based methods to understand the genotype-phenotype relationship for taste receptors. Human PROP sensitivity is determined by the combination of each of these 3 polymorphisms within the TAS2R38 gene.

SUBMITTER: Mennella JA

PROVIDER: S-EPMC3020389 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Psychophysical dissection of genotype effects on human bitter perception.

Mennella Julie A JA Pepino Marta Yanina MY Duke Fujiko F FF Reed Danielle R DR

Chemical senses 20101027 2

The purpose of this study was to define the effects of individual polymorphisms within the haplotypes of the TAS2R38 taste receptor gene on human bitter taste perception. A racially and ethnically diverse sample of children and adults (N = 980) was phenotyped for thresholds of 6-n-propylthiouracil (PROP) and genotyped for 3 polymorphisms of the TAS2R38 gene (A49P, V262A, I296V). Subjects were grouped according to their diplotype (i.e., specific combinations of haplotypes) and compared for PROP t ...[more]

PMID: 20980355

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Project description:BackgroundAlleles of the receptor gene TAS2R38 are responsible in part for the variation in bitter taste perception of 6-n-propylthiouracil (PROP) and structurally similar compounds (eg, glucosinolates in cruciferous vegetables). At low concentrations, people with the PAV ("taster" amino acid sequence) form of TAS2R38 perceive these bitter compounds, whereas most with the AVI ("nontaster" amino acid sequence) form do not; heterozygotes (PAV/AVI) show the widest range of bitter perception.ObjectivesThe objectives were to examine individual differences in expression of PAV-TAS2R38 messenger RNA (mRNA) among heterozygotes, to test the hypotheses that the abundance of allele-specific gene expression accounts for the variation in human bitter taste perception, and to relate to dietary intake of bitter-tasting beverages and foods.DesignHeterozygous individuals (n = 22) provided psychophysical evaluation of the bitterness of PROP, glucosinolate-containing broccoli juice, non-glucosinolate-containing carrot juice, and several bitter non-TAS2R38 ligands as well as dietary recalls. Fungiform taste papillae were examined for allele-specific TAS2R38 expression by using quantitative polymerase chain reaction.ResultsPAV-TAS2R38 mRNA expression was measured in 18 of 22 heterozygous subjects. Relative expression varied widely and positively correlated with ratings of bitterness intensity of PROP (P = 0.007) and broccoli juice (P = 0.004) but not of the control solutions carrot juice (P = 0.26), NaCl (P = 0.68), caffeine (P = 0.24), or urea (P = 0.47). Expression amounts were related to self-reported recent and habitual caffeine intake (P = 0.060, P = 0.005); vegetable intake was too low to analyze.ConclusionsWe provide evidence that PAV-TAS2R38 expression amount correlates with individual differences in bitter sensory perception and diet. The nature of this correlation calls for additional research on the molecular mechanisms associated with some individual differences in taste perception and food intake. The trial was registered at clinicaltrials.gov as NCT01399944.

Project description:Bitter taste stimuli are detected by a diverse family of G protein-coupled receptors (GPCRs) expressed in gustatory cells. Each bitter taste receptor (TAS2R) responds to an array of compounds, many of which are toxic and can be found in nature. For example, human TAS2R16 (hTAS2R16) responds to ?-glucosides such as salicin, and hTAS2R38 responds to thiourea-containing molecules such as glucosinolates and phenylthiocarbamide (PTC). While many substances are known to activate TAS2Rs, only one inhibitor that specifically blocks bitter receptor activation has been described. Here, we describe a new inhibitor of bitter taste receptors, p-(dipropylsulfamoyl)benzoic acid (probenecid), that acts on a subset of TAS2Rs and inhibits through a novel, allosteric mechanism of action. Probenecid is an FDA-approved inhibitor of the Multidrug Resistance Protein 1 (MRP1) transporter and is clinically used to treat gout in humans. Probenecid is also commonly used to enhance cellular signals in GPCR calcium mobilization assays. We show that probenecid specifically inhibits the cellular response mediated by the bitter taste receptor hTAS2R16 and provide molecular and pharmacological evidence for direct interaction with this GPCR using a non-competitive (allosteric) mechanism. Through a comprehensive analysis of hTAS2R16 point mutants, we define amino acid residues involved in the probenecid interaction that result in decreased sensitivity to probenecid while maintaining normal responses to salicin. Probenecid inhibits hTAS2R16, hTAS2R38, and hTAS2R43, but does not inhibit the bitter receptor hTAS2R31 or non-TAS2R GPCRs. Additionally, structurally unrelated MRP1 inhibitors, such as indomethacin, fail to inhibit hTAS2R16 function. Finally, we demonstrate that the inhibitory activity of probenecid in cellular experiments translates to inhibition of bitter taste perception of salicin in humans. This work identifies probenecid as a pharmacological tool for understanding the cell biology of bitter taste and as a lead for the development of broad specificity bitter blockers to improve nutrition and medical compliance.

Project description:Humans will eat almost anything, from caribou livers to rutabagas, but there are some types of foods, and their associated taste qualities, that are preferred by large groups of people regardless of culture or experience. When many choices are available, humans chose foods that taste good, that is, create pleasing sensations in the mouth. The concept of good taste for most people encompasses both flavor and texture of food, and these sensations merge with taste proper to form the concept of goodness. Although we acknowledge the universality of the goodness (sweet) or badness (bitter) of basic taste qualities, we also find that people differ, sometimes extremely so, in their ability to perceive and enjoy these qualities and, by extension, food and drink. The reasons for these differences among people are not clear but are probably due to a combination of experience beginning at an early age, perhaps in utero; learning, for example, as with conditioned taste aversions; sex and maturity; and perceptual differences that arise from genetic variation. In this review, we focus on individual variations that arise from genetic differences and review two domains of science: recent developments in the molecular biology of taste transduction, with a focus on the genes involved and second, studies that examine biological relatives to determine the heritability of taste perception. Because the receptors for sweet, savory (umami), and bitter have recently been discovered, we summarize what is known about their function by reviewing the effect of naturally occurring and man-made alleles of these receptors, their shape and function based on receptor modeling techniques, and how they differ across animal species that vary in their ability to taste certain qualities. We discuss this literature in the context of how taste genes may differ among people and give rise to individuated taste experience, and what is currently known about the genetic effects on taste perception in humans.

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Psychophysical dissection of genotype effects on human bitter perception.

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Psychophysical dissection of genotype effects on human bitter perception.

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