Differential Activation of TAS2R4 May Recover Ability to Taste Propylthiouracil for Some TAS2R38 AVI Homozygotes

Alissa A Nolden; Maik Behrens; John E McGeary; Wolfgang Meyerhof; John E Hayes

doi:10.3390/nu16091357

Differential Activation of TAS2R4 May Recover Ability to Taste Propylthiouracil for Some TAS2R38 AVI Homozygotes

Nutrients. 2024 Apr 30;16(9):1357. doi: 10.3390/nu16091357.

Authors

Alissa A Nolden^{1

2

3}, Maik Behrens^{4

5}, John E McGeary^{6

7}, Wolfgang Meyerhof^{4

8}, John E Hayes^{2

3}

Affiliations

¹ Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA.
² Sensory Evaluation Center, The Pennsylvania State University, University Park, PA 16802, USA.
³ Department of Food Science, The Pennsylvania State University, University Park, PA 16802, USA.
⁴ German Institute of Human Nutrition Potsdam-Rehbruecke, Department Molecular Genetics, 14558 Nuthetal, Germany.
⁵ Leibniz Institute for Food Systems Biology, Technical University of Munich, 85354 Freising, Germany.
⁶ Center of Innovation in Long Term Services & Supports, VA Providence Healthcare, Providence, RI 02908, USA.
⁷ Department of Psychiatry & Human Behavior, Alpert Medical School of Brown University, Providence, RI 02903, USA.
⁸ Center for Integrative Physiology and Molecular Medicine, Saarland University, 66424 Homburg, Germany.

Abstract

Bitterness from phenylthiocarbamide and 6-n-propylthiouracil (PROP) varies with polymorphisms in the TAS2R38 gene. Three SNPs form two common (AVI, PAV) and four rare haplotypes (AAI, AAV, PVI, and PAI). AVI homozygotes exhibit higher detection thresholds and lower suprathreshold bitterness for PROP compared to PAV homozygotes and heterozygotes, and these differences may influence alcohol and vegetable intake. Within a diplotype, substantial variation in suprathreshold bitterness persists, and some AVI homozygotes report moderate bitterness at high concentrations. A second receptor encoded by a gene containing a functional polymorphism may explain this. Early work has suggested that PROP might activate TAS2R4 in vitro, but later work did not replicate this. Here, we identify three TAS2R4 SNPs that result in three diplotypes-SLN/SLN, FVS/SLN, and FVS/FVS-which make up 25.1%, 44.9%, and 23.9% of our sample. These TAS2R4 haplotypes show minimal linkage disequilibrium with TAS2R38, so we examined the suprathreshold bitterness as a function of both. The participants (n = 243) rated five PROP concentrations in duplicate, interleaved with other stimuli. As expected, the TAS2R38 haplotypes explained ~29% (p < 0.0001) of the variation in the bitterness ratings, with substantial variation within the haplotypes (AVI/AVI, PAV/AVI, and PAV/PAV). Notably, the TAS2R4 diplotypes (independent of the TAS2R38 haplotypes) explained ~7-8% of the variation in the bitterness ratings (p = 0.0001). Given this, we revisited if PROP could activate heterologously expressed TAS2R4 in HEK293T cells, and calcium imaging indicated 3 mM PROP is a weak TAS2R4 agonist. In sum, our data are consistent with the second receptor hypothesis and may explain the recovery of the PROP tasting phenotype in some AVI homozygotes; further, this finding may potentially help explain the conflicting results on the TAS2R38 diplotype and food intake.

Keywords: genetic variation; individual differences; phenylthiocarbamide; propylthiouracil; psychophysics; supertasting; suprathreshold.

MeSH terms

Adult
Female
Haplotypes*
Homozygote
Humans
Male
Polymorphism, Single Nucleotide*
Propylthiouracil*
Receptors, G-Protein-Coupled* / genetics
Receptors, G-Protein-Coupled* / metabolism
Taste Threshold / genetics
Taste* / genetics
Young Adult

Substances

Propylthiouracil
Receptors, G-Protein-Coupled
taste receptors, type 2

Grants and funding

5R03DC101904-03A1/NH/NIH HHS/United States