Expression, Regulation and Putative Nutrient-Sensing Function of Taste GPCRs in the Heart

Foster, Simon R.; Porrello, Enzo R.; Purdue, Brooke W.; Chan, Hsiu‐Wen; Voigt, Anja; Frenzel, Sabine; Hannan, Ross D.; Moritz, Karen M.; Simmons, David G.; Molenaar, Peter; Roura, Eugeni; Boehm, Ulrich; Meyerhof, Wolfgang; Thomas, Walter G.

doi:10.1371/journal.pone.0064579

Cited by 124 publications

(157 citation statements)

References 46 publications

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“…These associations, prevalent in both cohorts, highlight a common module of G protein-coupled receptors that have been previously observed to be expressed in the healthy and failing heart 23,24 and that may play a role in contraction 25 .…”

Section: Network-enhanced Expression Profiles Reveal Novel Cis and Trsupporting

confidence: 61%

“…In some cases, the expression of entire subnetworks of genes were found to be associated with only a few variants, such as several members of the TAS2R G protein coupled receptor family, receptors typically associated with the sensation of taste but recently found to be variously expressed in cardiac tissue. 23 Further, these eQTLs were enriched for regulatory annotations, which were more prevalent in the failing heart cohort.…”

Section: Discussionmentioning

confidence: 99%

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Pathologic gene network rewiring implicates PPP1R3A as a central cardioprotective factor in pressure overload heart failure

Cordero

Erbilgin

et al. 2016

Preprint

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Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvested 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtained genome-wide genotyping and gene expression measurements for a subset of 313. We built failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerged as a novel regulator whose network connectivity changed significantly between health and disease. Time-course RNA sequencing after PPP1R3A knock-down validated network-based predictions of metabolic pathway expression, increased cardiomyocyte size, and perturbed respiratory metabolism. Mice lacking PPP1R3A were protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify new cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a novel central protective regulator in heart failure.

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Section: Network-enhanced Expression Profiles Reveal Novel Cis and Trsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Pathologic gene network rewiring implicates PPP1R3A as a central cardioprotective factor in pressure overload heart failure

Cordero

Erbilgin

et al. 2016

Preprint

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“…Recently, quantitative expression analyses of rodent Tas2r have been performed in non-gustatory tissues such as testis and heart (60,61). In mouse testis the highest expression was observed for Tas2r113 and Tas2r124, which showed low to moderate expression levels in gustatory tissue (Fig.…”

Section: Discussionmentioning

confidence: 98%

Comprehensive Analysis of Mouse Bitter Taste Receptors Reveals Different Molecular Receptive Ranges for Orthologous Receptors in Mice and Humans

Lossow

Hübner

Roudnitzky

et al. 2016

Journal of Biological Chemistry

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One key to animal survival is the detection and avoidance of potentially harmful compounds by their bitter taste. Variable numbers of taste 2 receptor genes expressed in the gustatory end organs enable bony vertebrates (Euteleostomi) to recognize numerous bitter chemicals. It is believed that the receptive ranges of bitter taste receptor repertoires match the profiles of bitter chemicals that the species encounter in their diets. Human and mouse genomes contain pairs of orthologous bitter receptor genes that have been conserved throughout evolution. Moreover, expansions in both lineages generated species-specific sets of bitter taste receptor genes. It is assumed that the orthologous bitter taste receptor genes mediate the recognition of bitter toxins relevant for both species, whereas the lineagespecific receptors enable the detection of substances differently encountered by mice and humans. By challenging 34 mouse bitter taste receptors with 128 prototypical bitter substances in a heterologous expression system, we identified cognate compounds for 21 receptors, 19 of which were previously orphan receptors. We have demonstrated that mouse taste 2 receptors, like their human counterparts, vary greatly in their breadth of tuning, ranging from very broadly to extremely narrowly tuned receptors. However, when compared with humans, mice possess fewer broadly tuned receptors and an elevated number of narrowly tuned receptors, supporting the idea that a large receptor repertoire is the basis for the evolution of specialized receptors. Moreover, we have demonstrated that sequence-orthologous bitter taste receptors have distinct agonist profiles. Species-specific gene expansions have enabled further diversification of bitter substance recognition spectra.The plethora of natural compounds that taste bitter for humans comprises numerous chemicals with pharmacological activities that can make them powerful toxins, such as the alkaloids strychnine and colchicine or the sesquiterpene lactone picrotoxinin (1). However, compounds believed to exert health-beneficial effects such as the antioxidative phytoestrogen genistein from soy (2), the analgesic drug acetaminophen (3), or various polyphenols also taste bitter (4). To avoid ingestion of bitter substances that would pose a threat to organisms, efficient recognition and rejection mechanisms have developed throughout the animal kingdom. In bony vertebrates (Euteleostomi), the avoidance of bitter compounds is centered on taste receptors that detect potentially harmful substances with high accuracy and adequate sensitivity (5). Vertebrate bitter taste receptors, called taste 2 receptors (TAS2R (human) or Tas2r (murine)), 2 are G protein-coupled receptors only remotely related to other classes of this large and enormously versatile receptor family (6 -10). During evolution the first Tas2r genes appeared in the genomes of bony fish (11). In higher vertebrates frequent independent expansions and pseudogenization events resulted in differently sized Tas2r gene repertoires (12). Cons...

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“…In humans, TAS2Rs belong to a family of 25 functional members that are clustered on chromosomes 5, 7, and 12 (1,4). TAS2Rs are expressed in various organs, including the gustatory organs, gastrointestinal tract, thyroid gland, respiratory organs, kidney, central nervous system, skin, and reproductive organs (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Many genetic polymorphisms have been identified for TAS2Rs, some of which are known to cause functional changes in bitter-taste sensitivity.…”

mentioning

confidence: 99%

Genotyping Analysis of Bitter-Taste Receptor Genes <i>TAS2R38</i> and <i>TAS2R46</i> in Japanese Patients with Gastrointestinal Cancers

Yamaki

Saito

Isono

et al. 2017

Journal of Nutritional Science and Vitaminology, J Nutr Sci Vit

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Summary Type-2 bitter-taste receptors (TAS2Rs) are important for the evaluation of food quality and the nutritional control in animals. Mutations in some TAS2Rs including TAS2R38 are known to increase susceptibility to various diseases. However, the involvement of TAS2Rs in cancers has not been well understood. We conducted a pilot study by genotyping two TAS2R genes, TAS2R38 and TAS2R46, in Japanese cancer patients diagnosed with the following types of cancer: biliary tract cancer, hepatocellular carcinoma, pancreatic cancer, colorectal cancer and gastric cancer. We selected the two TAS2Rs because they carry virtually non-functional alleles in human populations. We found that cancer risk is not associated with any TAS2R46 genotypes since there were no significant differences in genotype frequencies between cancer patients and controls. On the other hand, we confirmed that phenylthiocarbamide (PTC) non-tasters homozygous (AVI/AVI) for TAS2R38 were more frequent among Japanese cancer patients than those among controls as suggested in a previous study. The AVI/AVI genotype was therefore considered to increases cancer risk. In contrast, we also found that homozygous (PAV/PAV) PTC tasters are less frequent among cancer patients, suggesting that the PAV/PAV is a cancer resistant genotype that decreases cancer risk. Genotype frequencies for heterozygous AVI/PAV genotype were not significantly different between the two groups. It is suggested that the risk and resistance of cancers is antagonistically controlled by the two TAS2R38 alleles, PAV and AVI, rather than by the AVI allele alone.

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Expression, Regulation and Putative Nutrient-Sensing Function of Taste GPCRs in the Heart

Cited by 124 publications

References 46 publications

Pathologic gene network rewiring implicates PPP1R3A as a central cardioprotective factor in pressure overload heart failure

Pathologic gene network rewiring implicates PPP1R3A as a central cardioprotective factor in pressure overload heart failure

Comprehensive Analysis of Mouse Bitter Taste Receptors Reveals Different Molecular Receptive Ranges for Orthologous Receptors in Mice and Humans

Genotyping Analysis of Bitter-Taste Receptor Genes <i>TAS2R38</i> and <i>TAS2R46</i> in Japanese Patients with Gastrointestinal Cancers

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