Development of full sweet, umami, and bitter taste responsiveness requires Regulator of G protein Signaling-21 (RGS21).

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Development of full sweet, umami, and bitter taste responsiveness requires Regulator of G protein Signaling-21 (RGS21).

Chem Senses. 2018 Apr 26;:

Authors: Schroer AB, Gross JD, Kaski SW, Wix K, Siderovski DP, Vandenbeuch A, Setola V

Abstract
The mammalian tastes of sweet, umami, and bitter are initiated by activation of G protein-coupled receptors (GPCRs) of the T1R and T2R families on taste receptor cells. GPCRs signal via nucleotide exchange and hydrolysis, the latter hastened by GTPase-accelerating proteins (GAPs) that include the Regulators of G protein Signaling (RGS) protein family. We previously reported that RGS21, uniquely expressed in Type II taste receptor cells, decreases the potency of bitter-stimulated T2R signaling in cultured cells, consistent with its in vitro GAP activity. However, the role of RGS21 in organismal responses to GPCR-mediated tastants was not established. Here, we characterized mice lacking the Rgs21 fifth exon. Eliminating Rgs21 expression had no effect on body mass accumulation (a measure of alimentation), fungiform papillae number and morphology, circumvallate papillae morphology, and taste bud number. Two-bottle preference tests, however, revealed that Rgs21-null mice have blunted aversion to quinine and denatonium, and blunted preference for monosodium glutamate, the sweeteners sucrose and SC45647, and (surprisingly) NaCl. Observed reductions in GPCR-mediated tastant responses upon Rgs21 loss are opposite to original expectations, given that loss of RGS21 -- a GPCR signaling negative regulator -- should lead to increased responsiveness to tastant-mediated GPCR signaling (all else being equal). Yet, reduced organismal tastant responses are consistent with observations of reduced chorda tympani nerve recordings in Rgs21-null mice. Reduced tastant-mediated responses and behaviors exhibited by adult mice lacking Rgs21 expression since birth have thus revealed an underappreciated requirement for a GPCR GAP to establish the full character of tastant signaling.

PMID: 29701767 [PubMed - as supplied by publisher]

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Odor-Cued Bitter Taste Avoidance.

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Odor-Cued Bitter Taste Avoidance.

Chem Senses. 2018 Apr 23;43(4):239-247

Authors: Coppola DM, Slotnick B

Abstract
In the course of our ongoing studies of odor-cued taste avoidance (OCTA) to measure olfactory capabilities in animals, we observed that mice could rapidly learn to use the vapor of the classical bitterant quinine hydrochloride to avoid contact with the tastant. Here we expand on this observation to determine which among several compounds generally classed as bitter could be detected at a distance. Since mice were initially naïve we were able to assess whether the vapors of the bitter compounds tested were innately aversive as are their tastes. CD-1 mice could readily use vapor cues from quinine hydrochloride, denatonium benzoate (DB), and 6-propyl-2-thiouracil to avoid their taste. Although mice did not hesitate to make contact with these solutions on their first exposure, they did learn to do so typically after only 1 or 2 exposures. Bilaterally bulbectomized mice did not learn or retain the ability to avoid quinine and DB solutions by vapor alone, implicating olfaction as the mode of detection. Saturated aqueous solutions of sucrose octaacetate and caffeine which are bitter to humans and some strains of mice were not aversive in our studies. The very low vapor concentrations of the 3 bitterant solutions that mice detected at a distance, suggest that impurities in the reagent grade solutions, rather than the bitter molecules themselves were the basis of detection. Implications of these findings for taste testing and the role of odor in food acceptance/rejections decisions are discussed.

PMID: 29688449 [PubMed - in process]

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CALHM3 Is Essential for Rapid Ion Channel-Mediated Purinergic Neurotransmission of GPCR-Mediated Tastes.

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CALHM3 Is Essential for Rapid Ion Channel-Mediated Purinergic Neurotransmission of GPCR-Mediated Tastes.

Neuron. 2018 Apr 13;:

Authors: Ma Z, Taruno A, Ohmoto M, Jyotaki M, Lim JC, Miyazaki H, Niisato N, Marunaka Y, Lee RJ, Hoff H, Payne R, Demuro A, Parker I, Mitchell CH, Henao-Mejia J, Tanis JE, Matsumoto I, Tordoff MG, Foskett JK

Abstract
Binding of sweet, umami, and bitter tastants to G protein-coupled receptors (GPCRs) in apical membranes of type II taste bud cells (TBCs) triggers action potentials that activate a voltage-gated nonselective ion channel to release ATP to gustatory nerves mediating taste perception. Although calcium homeostasis modulator 1 (CALHM1) is necessary for ATP release, the molecular identification of the channel complex that provides the conductive ATP-release mechanism suitable for action potential-dependent neurotransmission remains to be determined. Here we show that CALHM3 interacts with CALHM1 as a pore-forming subunit in a CALHM1/CALHM3 hexameric channel, endowing it with fast voltage-activated gating identical to that of the ATP-release channel in vivo. Calhm3 is co-expressed with Calhm1 exclusively in type II TBCs, and its genetic deletion abolishes taste-evoked ATP release from taste buds and GPCR-mediated taste perception. Thus, CALHM3, together with CALHM1, is essential to form the fast voltage-gated ATP-release channel in type II TBCs required for GPCR-mediated tastes.

PMID: 29681531 [PubMed - as supplied by publisher]

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A synthetic biology-based device prevents liver injury in mice.

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A synthetic biology-based device prevents liver injury in mice.

J Hepatol. 2016 Jul;65(1):84-94

Authors: Bai P, Ye H, Xie M, Saxena P, Zulewski H, Charpin-El Hamri G, Djonov V, Fussenegger M

Abstract
BACKGROUND & AIMS: The liver performs a panoply of complex activities coordinating metabolic, immunologic and detoxification processes. Despite the liver's robustness and unique self-regeneration capacity, viral infection, autoimmune disorders, fatty liver disease, alcohol abuse and drug-induced hepatotoxicity contribute to the increasing prevalence of liver failure. Liver injuries impair the clearance of bile acids from the hepatic portal vein which leads to their spill over into the peripheral circulation where they activate the G-protein-coupled bile acid receptor TGR5 to initiate a variety of hepatoprotective processes.
METHODS: By functionally linking activation of ectopically expressed TGR5 to an artificial promoter controlling transcription of the hepatocyte growth factor (HGF), we created a closed-loop synthetic signalling network that coordinated liver injury-associated serum bile acid levels to expression of HGF in a self-sufficient, reversible and dose-dependent manner.
RESULTS: After implantation of genetically engineered human cells inside auto-vascularizing, immunoprotective and clinically validated alginate-poly-(L-lysine)-alginate beads into mice, the liver-protection device detected pathologic serum bile acid levels and produced therapeutic HGF levels that protected the animals from acute drug-induced liver failure.
CONCLUSIONS: Genetically engineered cells containing theranostic gene circuits that dynamically interface with host metabolism may provide novel opportunities for preventive, acute and chronic healthcare.
LAY SUMMARY: Liver diseases leading to organ failure may go unnoticed as they do not trigger any symptoms or significant discomfort. We have designed a synthetic gene circuit that senses excessive bile acid levels associated with liver injuries and automatically produces a therapeutic protein in response. When integrated into mammalian cells and implanted into mice, the circuit detects the onset of liver injuries and coordinates the production of a protein pharmaceutical which prevents liver damage.

PMID: 27067456 [PubMed - indexed for MEDLINE]

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Aggravated gut inflammation in mice lacking the taste signaling protein α-gustducin.

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Aggravated gut inflammation in mice lacking the taste signaling protein α-gustducin.

Brain Behav Immun. 2018 Apr 17;:

Authors: Feng P, Chai J, Yi H, Redding K, Margolskee RF, Huang L, Wang H

Abstract
Inflammatory bowel disease (IBD) is a debilitating immune-related condition that affects over 1.4 million Americans. Recent studies indicate that taste receptor signaling is involved in much more than sensing food flavor, and taste receptors have been localized in a variety of extra-oral tissues. One of the newly revealed functions of taste receptors and downstream signaling proteins is modulation of immune responses to microbes and parasites. We previously found that components of the taste receptor signaling pathway are expressed in subsets of the intestinal epithelial cells. α-Gustducin, a key G-protein α subunit involved in sweet, umami, and bitter taste receptor signaling, is expressed in the intestinal mucosa. In this study, we investigated the role of α-gustducin in regulation of gut mucosal immunity and inflammation using α-gustducin knockout mice in the dextran sulfate sodium (DSS)-induced IBD model. DSS is a chemical colitogen that can cause intestinal epithelial damage and inflammation. We analyzed DSS-induced colitis in α-gustducin knockout versus wild-type control mice after administration of DSS in drinking water. Our results show that the knockout mice had aggravated weight loss, diarrhea, intestinal bleeding, and inflammation over the experimental period compared to wild-type mice, concurrent with augmented immune cell infiltration and increased expression of TNF and IFN-γ but decreased expression of IL-13 and IL-5 in the colon. These results suggest that the taste receptor signaling pathway may play critical roles in regulating gut immune balance and inflammation.

PMID: 29678794 [PubMed - as supplied by publisher]

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A Multispecific Investigation of the Metal Effect in Mammalian Odorant Receptors for Sulfur-containing Compounds.

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A Multispecific Investigation of the Metal Effect in Mammalian Odorant Receptors for Sulfur-containing Compounds.

Chem Senses. 2018 Apr 06;:

Authors: Zhang R, Pan Y, Ahmed L, Block E, Zhang Y, Batista VS, Zhuang H

Abstract
Metal-coordinating compounds are generally known to have strong smells, a phenomenon that can be attributed to the fact that odorant receptors for intense-smelling compounds, such as those containing sulfur, may be metalloproteins. We previously identified a mouse OR, Olfr1509, that requires copper ions for sensitive detection of a series of metal-coordinating odorants, including (methylthio)methanethiol (MTMT), a strong-smelling component of male mouse urine that attracts female mice. By combining mutagenesis and QM/MM modeling, we identified candidate binding sites in Olfr1509 that may bind to the copper-MTMT complex. However, whether there are other receptors utilizing metal ions for ligand-binding and other sites important for receptor activation is still unknown. In this study, we describe a second mouse OR for MTMT with a copper effect, namely Olfr1019. In an attempt to investigate the functional changes of metal-coordinating ORs in multiple species and to decipher additional sites involved in the metal effect, we cloned various mammalian orthologs of the two mouse MTMT receptors, and a third mouse MTMT receptor, Olfr15, that does not have a copper effect. We found that the function of all three MTMT receptors varies greatly among species and that the response to MTMT always co-occurred with the copper effect. Furthermore, using ancestral reconstruction and QM/MM modeling combined with receptor functional assay, we found that the amino acid residue R260 in Olfr1509 and the respective R261 site in Olfr1019 may be important for receptor activation.

PMID: 29659735 [PubMed - as supplied by publisher]

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An enduring legacy: Dr. Alina Szczesniak's classification of food texture.

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An enduring legacy: Dr. Alina Szczesniak's classification of food texture.

J Texture Stud. 2018 Apr 16;:

Authors: Christensen CM

PMID: 29659019 [PubMed - as supplied by publisher]

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The Role of Quinine-Responsive Taste Receptor Family 2 in Airway Immune Defense and Chronic Rhinosinusitis.

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The Role of Quinine-Responsive Taste Receptor Family 2 in Airway Immune Defense and Chronic Rhinosinusitis.

Front Immunol. 2018;9:624

Authors: Workman AD, Maina IW, Brooks SG, Kohanski MA, Cowart BJ, Mansfield C, Kennedy DW, Palmer JN, Adappa ND, Reed DR, Lee RJ, Cohen NA

Abstract
Background: Bitter (T2R) and sweet (T1R) taste receptors in the airway are important in innate immune defense, and variations in taste receptor functionality in one T2R (T2R38) correlate with disease status and disease severity in chronic rhinosinusitis (CRS). Quinine is a bitter compound that is an agonist for several T2Rs also expressed on sinonasal cells, but not for T2R38. Because of this property, quinine may stimulate innate immune defense mechanisms in the airway, and functional differences in quinine perception may be reflective of disease status in CRS.
Methods: Demographic and taste intensity data were collected prospectively from CRS patients and non-CRS control subjects. Sinonasal tissue from patients undergoing rhinologic surgery was also collected and grown at an air-liquid interface (ALI). Nitric oxide (NO) production and dynamic regulation of ciliary beat frequency in response to quinine stimulation were assessed in vitro.
Results: Quinine reliably increased ciliary beat frequency and NO production in ALI cultures in a manner consistent with T2R activation (p < 0.01). Quinine taste intensity rating was performed in 328 CRS patients and 287 control subjects demonstrating that CRS with nasal polyps (CRSwNP) patients rated quinine as significantly less intense than did control subjects.
Conclusion: Quinine stimulates airway innate immune defenses by increasing ciliary beat frequency and stimulating NO production in a manner fitting with T2R activation. Patient variability in quinine sensitivity is observed in taste intensity ratings, and gustatory quinine "insensitivity" is associated with CRSwNP status. Thus, taste tests for quinine may be a biomarker for CRSwNP, and topical quinine has therapeutic potential as a stimulant of innate defenses.

PMID: 29643854 [PubMed]

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Use of Adult Sensory Panel to Study Individual Differences in the Palatability of a Pediatric HIV Treatment Drug.

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Use of Adult Sensory Panel to Study Individual Differences in the Palatability of a Pediatric HIV Treatment Drug.

Clin Ther. 2017 Oct;39(10):2038-2048

Authors: Mennella JA, Mathew PS, Lowenthal ED

Abstract
PURPOSE: The recommended first-line treatment for young children infected with HIV includes the liquid formulation of the co-formulated protease inhibitors lopinavir/ritonavir (Kaletra® [Abbott Laboratories, Chicago, Illinois]). Clinical reports indicate that some children readily accept the taste of Kaletra, whereas others strongly reject it, which can deter therapeutic adherence and outcomes.
METHODS: As a proof-of-concept approach, a sensory panel of genotyped adults was used to document the range of individual differences in the taste and palatability (hedonics) of the liquid formulation of Kaletra and other taste stimuli, including common excipients. Panelists rated taste sensations using generalized labeled magnitude scales to determine genotype-phenotype relationships. Several months later, the panelists were retested to assess response reliability.
FINDINGS: Not all panelists had the same sensory experience when tasting Kaletra. Palatability ratings varied widely, from moderate like to strongest imaginable dislike, and were reliable over time. The more irritating and bitter Kaletra tasted, the more disliked by the panelist. The more they disliked the taste of Kaletra, the more they disliked the taste of its excipient ethanol and the bitter stimulus denatonium. Those who experienced less bitter and sweeter taste sensations had a different genetic signature than the other panelists. Bitterness and irritation ratings of Kaletra varied by the orphaned bitter receptor gene (TAS2R60), whereas sweetness ratings of Kaletra varied according to the cold receptor gene (TRPM8), which is activated by menthol, an excipient of Kaletra. Neither genotype related to ratings for ethanol or denatonium, however.
IMPLICATIONS: The use of a sensory panel holds promise as a first step in determining the nature of individual differences in the palatability of existing pediatric drug formulations and sources of variation. In this era of personalized medicine, the need is great to develop psychophysical tools to determine which drugs will show variation in acceptance by children and whether patterns of individual variation in taste as assessed by adults mirror those of young patients. ClinicalTrials.gov identifier: NCT01841710.

PMID: 28923290 [PubMed - indexed for MEDLINE]

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