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2.
Biosci Biotechnol Biochem ; 85(11): 2295-2299, 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34468713

RESUMO

Human susceptibility to NaCl varies depending on temperature and pH, the molecular mechanisms of which remain unclear. The voltage-dependent chloride channel, transmembrane channel-like 4 (TMC4), is activated at approximately 40 °C and is suppressed at pH 5.5. As these are similar in character to human sensory evaluations, human TMC4 may be involved in human salt taste reception.

3.
Curr Biol ; 31(20): 4641-4649.e5, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34450087

RESUMO

Taste perception plays an essential role in food selection. Umami (savory) tastes are sensed by a taste receptor complex, T1R1/T1R3, that detects proteinogenic amino acids.1 High sensitivity to l-glutamate (l-Glu) is a characteristic of human T1R1/T1R3, but the T1R1/T1R3 of other vertebrates does not consistently show this l-Glu response.1,2 Here, we demonstrate that the l-Glu sensitivity of T1R1/T1R3 is a derived state that has evolved repeatedly in large primates that rely on leaves as protein sources, after their divergence from insectivorous ancestors. Receptor expression experiments show that common amino acid substitutions at ligand binding sites that render T1R1/T1R3 sensitive to l-Glu occur independently at least three times in primate evolution. Meanwhile T1R1/T1R3 senses 5'-ribonucleotides as opposed to l-Glu in several mammalian species, including insectivorous primates. Our chemical analysis reveal that l-Glu is one of the major free amino acids in primate diets and that insects, but not leaves, contain large amounts of free 5'-ribonucleotides. Altering the ligand-binding preference of T1R1/T1R3 from 5'-ribonucleotides to l-Glu might promote leaf consumption, overcoming bitter and aversive tastes. Altogether, our results provide insight into the foraging ecology of a diverse mammalian radiation and help reveal how evolution of sensory genes facilitates invasion of new ecological niches.

4.
Biochem Biophys Res Commun ; 573: 76-79, 2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34411898

RESUMO

Nonsteroidal anti-inflammatory drugs, such as ibuprofen, are known to modify salty taste perception in humans. However, the underlying molecular mechanisms remain unknown. We investigated the inhibitory effect of ibuprofen on the NaCl stimulation of epithelium sodium channel (ENaC) and transmembrane channel-like 4 (TMC4), which are involved in salty taste detection. Although ibuprofen only minimally inhibited the response of the ENaC to NaCl, it significantly inhibited the TMC4 response to NaCl with an IC50 at 1.45 mM. These results suggest that ibuprofen interferes with detection of salty taste via inhibition of TMC4.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Ibuprofeno/farmacologia , Proteínas de Membrana/antagonistas & inibidores , Cloreto de Sódio/administração & dosagem , Administração Oral , Humanos , Proteínas de Membrana/metabolismo , Percepção Gustatória/efeitos dos fármacos
5.
J Physiol Sci ; 71(1): 23, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34429071

RESUMO

"Salty taste" sensation is evoked when sodium and chloride ions are present together in the oral cavity. The presence of an epithelial cation channel that receives Na+ has previously been reported. However, no molecular entity involving Cl- receptors has been elucidated. We report the strong expression of transmembrane channel-like 4 (TMC4) in the circumvallate and foliate papillae projected to the glossopharyngeal nerve, mediating a high-concentration of NaCl. Electrophysiological analysis using HEK293T cells revealed that TMC4 was a voltage-dependent Cl- channel and the consequent currents were completely inhibited by NPPB, an anion channel blocker. TMC4 allowed permeation of organic anions including gluconate, but their current amplitudes at positive potentials were less than that of Cl-. Tmc4-deficient mice showed significantly weaker glossopharyngeal nerve response to high-concentration of NaCl than the wild-type littermates. These results indicated that TMC4 is a novel chloride channel that responds to high-concentration of NaCl.

6.
J Agric Food Chem ; 69(33): 9585-9596, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34346218

RESUMO

Inhibiting apical sodium-dependent bile acid transporter (ASBT) has been identified as a potential strategy to reduce plasma cholesterol levels. Thus, in this study, we aimed to identify polyphenols that inhibited ASBT activity and to elucidate their mechanism. ASBT is responsible for most of the taurocholic acid (TC) uptake in Caco-2 cells. Of the 39 polyphenols examined, theaflavin (TF)-3-gallate (TF2A) and theaflavin-3'-gallate (TF2B) have been found to significantly reduce TC uptake in Caco-2 cells to 37.4 ± 2.8 and 33.8 ± 4.0%, respectively, of that in the untreated cells. The results from the TC uptake assay using N-acetylcysteine suggested that the inhibitory effect of TF2A and TF2B was attributed to the oxidization of their benzotropolone rings and their covalent bonding with ASBT's cysteine. TC uptake was reduced in the COS-7 cells expressing recombinant ASBT whose cysteine residues were mutated to alanine. Finally, the substrate concentration-dependent TC uptake assay showed that TFs competitively inhibited TC uptake.


Assuntos
Biflavonoides/farmacologia , Catequina/farmacologia , Transportadores de Ânions Orgânicos Dependentes de Sódio , Simportadores , Ácidos e Sais Biliares , Células CACO-2 , Humanos , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Simportadores/antagonistas & inibidores , Simportadores/genética , Ácido Taurocólico/metabolismo
7.
Science ; 373(6551): 226-231, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244416

RESUMO

Early events in the evolutionary history of a clade can shape the sensory systems of descendant lineages. Although the avian ancestor may not have had a sweet receptor, the widespread incidence of nectar-feeding birds suggests multiple acquisitions of sugar detection. In this study, we identify a single early sensory shift of the umami receptor (the T1R1-T1R3 heterodimer) that conferred sweet-sensing abilities in songbirds, a large evolutionary radiation containing nearly half of all living birds. We demonstrate sugar responses across species with diverse diets, uncover critical sites underlying carbohydrate detection, and identify the molecular basis of sensory convergence between songbirds and nectar-specialist hummingbirds. This early shift shaped the sensory biology of an entire radiation, emphasizing the role of contingency and providing an example of the genetic basis of convergence in avian evolution.


Assuntos
Evolução Biológica , Néctar de Plantas , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Aves Canoras/fisiologia , Percepção Gustatória , Aminoácidos , Animais , Proteínas Aviárias/química , Proteínas Aviárias/metabolismo , Aves/fisiologia , Carboidratos , Dieta , Comportamento Alimentar , Multimerização Proteica , Sacarose
8.
J Nutr Sci Vitaminol (Tokyo) ; 67(3): 196-200, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34193679

RESUMO

Taste is a chemical sensation that primarily detects nutrients present in food, and maintenance of taste sensations is important for ensuring that older people have a balanced nutritional diet. While several reports have suggested that taste sensitivity changes with age, the molecular mechanisms underlying this phenomenon are still unclear. Previous studies on the matter have focused mainly on the relationship between aging and taste detection of specific basic taste-inducing substances, and other than for these basic substances, understanding of how aging affects the detection of taste is limited. Therefore, to understand the effect that aging has on the taste detection of some familiar substances found in our daily meals, namely capsaicin and catechin, we investigated age-related changes in taste preferences to capsaicin and catechin in young and old C57BL/6J mice using a 48-h two-bottle preference test. For the capsaicin stimuli, the mice showed avoidance behavior in a concentration-dependent manner. However, we observed that there was no significant difference in the preference ratio for capsaicin between young and old mice. For the catechin stimuli, although both age groups showed avoidance behavior in a concentration-dependent manner, the preference ratio in old mice showed significantly higher values than those in young mice. This suggests that catechin sensitivity is declined due to aging. Thus, we observed that catechin sensitivity decreases with age, but capsaicin sensitivity does not.


Assuntos
Catequina , Paladar , Envelhecimento , Animais , Capsaicina/farmacologia , Preferências Alimentares , Camundongos , Camundongos Endogâmicos C57BL
9.
BMC Genomics ; 22(1): 347, 2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-33985426

RESUMO

BACKGROUND: Curculigo latifolia is a perennial plant endogenous to Southeast Asia whose fruits contain the taste-modifying protein neoculin, which binds to sweet receptors and makes sour fruits taste sweet. Although similar to snowdrop (Galanthus nivalis) agglutinin (GNA), which contains mannose-binding sites in its sequence and 3D structure, neoculin lacks such sites and has no lectin activity. Whether the fruits of C. latifolia and other Curculigo plants contain neoculin and/or GNA family members was unclear. RESULTS: Through de novo RNA-seq assembly of the fruits of C. latifolia and the related C. capitulata and detailed analysis of the expression patterns of neoculin and neoculin-like genes in both species, we assembled 85,697 transcripts from C. latifolia and 76,775 from C. capitulata using Trinity and annotated them using public databases. We identified 70,371 unigenes in C. latifolia and 63,704 in C. capitulata. In total, 38.6% of unigenes from C. latifolia and 42.6% from C. capitulata shared high similarity between the two species. We identified ten neoculin-related transcripts in C. latifolia and 15 in C. capitulata, encoding both the basic and acidic subunits of neoculin in both plants. We aligned these 25 transcripts and generated a phylogenetic tree. Many orthologs in the two species shared high similarity, despite the low number of common genes, suggesting that these genes likely existed before the two species diverged. The relative expression levels of these genes differed considerably between the two species: the transcripts per million (TPM) values of neoculin genes were 60 times higher in C. latifolia than in C. capitulata, whereas those of GNA family members were 15,000 times lower in C. latifolia than in C. capitulata. CONCLUSIONS: The genetic diversity of neoculin-related genes strongly suggests that neoculin genes underwent duplication during evolution. The marked differences in their expression profiles between C. latifolia and C. capitulata may be due to mutations in regions involved in transcriptional regulation. Comprehensive analysis of the genes expressed in the fruits of these two Curculigo species helped elucidate the origin of neoculin at the molecular level.


Assuntos
Curculigo , Paladar , Curculigo/genética , Curculigo/metabolismo , Frutas/genética , Frutas/metabolismo , Perfilação da Expressão Gênica , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Edulcorantes , Transcriptoma
10.
PLoS One ; 16(3): e0248673, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33755681

RESUMO

Several studies have suggested that cognitive impairment affects taste sensitivity. However, the mechanism behind this is still unclear. In this study, we focused on short-term memory. Using senescence-accelerated mouse prone 1 (SAMP1) mice, we compared whether the effects of aging are observed earlier in taste sensitivity or short-term memory. We used 8-week-old mice as the young group, and 70- and 80-week-old mice as aged groups. Taste sensitivity was evaluated using a 48-hour two-bottle preference test, and short-term memory was evaluated using the Y-maze test. SAMP1 mice showed apparently changes in taste sensitivity at 70-weeks-old. However, the influence of aging on spontaneous alternation behavior, which is indicative of short-term memory alterations, was not observed in 70-week-old mice. At 80-weeks-old, the influence of aging was observed, and spontaneous alternation behavior was significantly decreased. This suggests that age-dependent changes in taste sensitivity occur prior to short-term memory function decline. In addition, there was no significant influence of aging on the mRNA expression of long-term potentiation-related genes in the hippocampus of 80-week-old mice. Therefore, the age-related decline of short-term memory may not affect taste sensitivity.


Assuntos
Envelhecimento , Memória de Curto Prazo , Paladar , Animais , Masculino , Camundongos
11.
ACS Omega ; 6(6): 4401-4407, 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33644553

RESUMO

Vegetables are important sources of nutrients and bioactive compounds; however, their consumption is often insufficient, partly because of unpleasant taste characteristics. This study aimed to investigate the mechanisms underlying bitter taste reception and to develop methods to suppress bitterness. We focused on sesquiterpene lactones found in edible Asteraceae species. HEK293T cells that heterologously expressed human bitter taste receptors (including TAS2R46) together with a chimeric G protein were analyzed using calcium imaging, and cellular responses to four sesquiterpene lactones contained in lettuce were examined. We found that TAS2R46-expressing cells responded most strongly to bitter compounds. The EC50 value of 11ß,13-dihydrolactucopicrin was 2.0 ± 0.6 µM, in agreement with the previously reported bitterness threshold of the compound. Adjustment of pH from neutral to weak acidic conditions reduced the response of TAS2R46-expressing cells to sesquiterpene lactones. We demonstrate the possibility of regulating the bitterness of Asteraceae species by controlling the pH.

12.
Biochem Biophys Res Commun ; 533(4): 704-709, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33160623

RESUMO

Matured hop bitter acids (MHBA) are bitter acid oxides derived from hops, widely consumed as food ingredients to add bitterness and flavor in beers. Previous studies have suggested a potential gut-brain mechanism in which MHBA simulates enteroendocrine cells to produce cholecystokinin (CCK), a gastrointestinal hormone which activates autonomic nerves, resulting in body fat reduction and cognitive improvement; however, the MHBA recognition site on enteroendocrine cells has not been fully elucidated. In this study, we report that MHBA is recognized by specific human and mouse bitter taste receptors (human TAS2R1, 8, 10 and mouse Tas2r119, 130, 105) using a heterologous receptor expression system in human embryonic kidney 293T cells. In addition, knockdown of each of these receptors using siRNA transfection partially but significantly suppressed an MHBA-induced calcium response and CCK production in enteroendocrine cells. Furthermore, blocking one of the essential taste signaling components, transient receptor potential cation channel subfamily M member 5, remarkably inhibited the MHBA-induced calcium response and CCK production in enteroendocrine cells. Our results demonstrate that specific bitter taste receptor activation by MHBA drives downstream calcium response and CCK production in enteroendocrine cells. These findings reveal a mechanism by which food ingredients derived from hops in beer activate the gut-brain axis for the first time.


Assuntos
Cerveja/análise , Colecistocinina/metabolismo , Células Enteroendócrinas/metabolismo , Hormônios Gastrointestinais/metabolismo , Humulus/química , Receptores Acoplados a Proteínas G/metabolismo , Animais , Cálcio/metabolismo , Linhagem Celular , Técnicas de Silenciamento de Genes , Humanos , Camundongos , RNA Interferente Pequeno , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais/fisiologia , Paladar
13.
Int J Mol Sci ; 21(19)2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32987926

RESUMO

Interaction between umami and bitter taste has long been observed in human sensory studies and in neural responses in animal models, however, the molecular mechanism for their action has not been delineated. Humans detect diverse bitter compounds using 25-30 members of the type 2 taste receptor (TAS2R) family of G protein-coupled receptor. In this study, we investigated the putative mechanism of antagonism by umami substances using HEK293T cells expressing hTAS2R16 and two known probenecid-insensitive mutant receptors, hTAS2R16 N96T and P44T. In wild type receptor, Glu-Glu, inosine monophosphate (IMP), and l-theanine behave as partial insurmountable antagonists, and monosodium glutamate (MSG) acts as a surmountable antagonist in comparison with probenecid as a full insurmountable antagonist. The synergism with IMP of umami substances still stands in the suppression of hTAS2R16 signaling. In mutagenesis analysis, we found that Glu-Glu, MSG, and l-theanine share at least one critical binding site on N96 and P44 with probenecid. These results provide the first evidence for a direct binding of umami substances to the hTAS2R16 through the probenecid binding pocket on the receptor, resulting in the suppression of bitterness.


Assuntos
Álcoois Benzílicos/metabolismo , Dipeptídeos/metabolismo , Glucosídeos/metabolismo , Glutamatos/metabolismo , Inosina Monofosfato/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Glutamato de Sódio/metabolismo , Inibidores de Ciclo-Oxigenase , Células HEK293 , Humanos , Ligação Proteica
14.
Chem Senses ; 45(8): 667-673, 2020 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-32832995

RESUMO

A sweet taste receptor is composed of heterodimeric G-protein-coupled receptors T1R2 and T1R3. Although there are many sweet tastants, only a few compounds have been reported as negative allosteric modulators (NAMs), such as lactisole, its structural derivative 2,4-DP, and gymnemic acid. In this study, candidates for NAMs of the sweet taste receptor were explored, focusing on the structural motif of lactisole. Ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID), has an α-methylacetic acid moiety, and this structure is also shared by lactisole and 2,4-DP. When ibuprofen was applied together with 1 mM aspartame to the cells that stably expressed the sweet taste receptor, it inhibited the receptor activity in a dose-dependent manner. The IC50 value of ibuprofen against the human sweet taste receptor was calculated as approximately 12 µM, and it was almost equal to that of 2,4-DP, which is known as the most potent NAM for the receptor to date. On the other hand, when the inhibitory activities of other profens were examined, naproxen also showed relatively potent NAM activity against the receptor. The results from both mutant analysis for the transmembrane domain (TMD) of T1R3 and docking simulation strongly suggest that ibuprofen and naproxen interact with T1R3-TMD, similar to lactisole and 2,4-DP. However, although 2,4-DP and ibuprofen had almost the same inhibitory activities, these activities were acquired by filling different spaces of the ligand pocket of T1R3-TMD; this knowledge could lead to the rational design of a novel NAM against the sweet taste receptor.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Ibuprofeno/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/química , Derivados de Benzeno/farmacologia , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Ibuprofeno/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Naproxeno/farmacologia
15.
Molecules ; 25(12)2020 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-32560345

RESUMO

Lactisole, which has a 2-phenoxy propionic acid skeleton, is well-known as an inhibitor of sweet taste receptors. We recently revealed some of the structure-activity relationships of the aromatic ring and chiral center of lactisole. Photoaffinity labeling is one of the common chemical biology methods to elucidate the interaction between bioactive compounds and biomolecules. In this paper, the novel asymmetric synthesis of lactisole derivatives with common photophores (benzophenone, azide and trifluoromethyldiazirine) for photoaffinity labeling is described. The synthetic compounds are subjected to cell-based sweet taste receptors, and the substitution with trifluoromethyldiazirinyl photophore shows the highest affinity to the receptor of the synthesized compounds.


Assuntos
Derivados de Benzeno , Corantes Fluorescentes , Receptores Acoplados a Proteínas G/metabolismo , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Linhagem Celular , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Humanos , Receptores Acoplados a Proteínas G/genética , Relação Estrutura-Atividade
16.
J Alzheimers Dis ; 76(3): 997-1004, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32568206

RESUMO

BACKGROUND: Some studies have reported a decline in taste sensitivities in patients with Alzheimer's disease. However, the detail remains unknown. OBJECTIVE: We investigated the effect of cognitive impairment on taste sensitivity using an App knock-in mouse model of Alzheimer's disease. METHODS: Behavioral assays, a brief access test, and a 48 h two-bottle preference test, to assess taste sensitivities were started from 12 months of age in mice that were confirmed to have impaired cognition. RESULTS: In the assays, there was no significant difference in taste sensitivities between wild type and App knock-in mice. Additionally, no apparent difference was observed in the expression of taste markers in their taste bud cells. CONCLUSION: We concluded that cognitive impairment might not greatly affect taste sensitivity.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Encéfalo/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Comportamento Animal , Modelos Animais de Doenças , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Camundongos Transgênicos , Placa Amiloide/genética , Placa Amiloide/metabolismo , Paladar
17.
Gerontology ; 66(3): 275-285, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31968334

RESUMO

α-Glycerophosphocholine (GPC) is a natural source of choline. It reportedly prevents aging-related decline in cognitive function, but the underlying mechanism remains unclear. Although it is understood that aging influences taste sensitivity and energy regulation, whether GPC exerts antiaging effects on such phenomena requires further elucidation. Here, we used old C57BL/6J mice that were fed a GPC-containing diet, to investigate the molecular mechanisms underlying the prevention of a decline in cognitive function associated with aging and examine the beneficial effects of GPC intake on aging-related phenomena, such as taste sensitivity and energy regulation. We confirmed that GPC intake reduces the aging-related decline in the expression levels of genes related to long-term potentiation. Although we did not observe an improvement in aging-related decline in taste sensitivity, there was a notable improvement in the expression levels of ß-oxidation-associated genes in old mice. Our results suggest that the prevention of aging-related decline in cognitive function by GPC intake may be associated with the improvement of gene expression levels of long-term potentiation. Furthermore, GPC intake may positively influence lipid metabolism.


Assuntos
Cognição/efeitos dos fármacos , Glicerilfosforilcolina/metabolismo , Paladar/efeitos dos fármacos , Envelhecimento/efeitos dos fármacos , Animais , Dieta , Suplementos Nutricionais , Expressão Gênica/efeitos dos fármacos , Glicerilfosforilcolina/farmacologia , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
18.
Nat Commun ; 10(1): 4560, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594935

RESUMO

The gustatory system plays a critical role in sensing appetitive and aversive taste stimuli for evaluating food quality. Although taste preference is known to change depending on internal states such as hunger, a mechanistic insight remains unclear. Here, we examine the neuronal mechanisms regulating hunger-induced taste modification. Starved mice exhibit an increased preference for sweetness and tolerance for aversive taste. This hunger-induced taste modification is recapitulated by selective activation of orexigenic Agouti-related peptide (AgRP)-expressing neurons in the hypothalamus projecting to the lateral hypothalamus, but not to other regions. Glutamatergic, but not GABAergic, neurons in the lateral hypothalamus function as downstream neurons of AgRP neurons. Importantly, these neurons play a key role in modulating preferences for both appetitive and aversive tastes by using distinct pathways projecting to the lateral septum or the lateral habenula, respectively. Our results suggest that these hypothalamic circuits would be important for optimizing feeding behavior under fasting.


Assuntos
Habenula/fisiologia , Fome/fisiologia , Região Hipotalâmica Lateral/fisiologia , Núcleos Septais/fisiologia , Paladar/fisiologia , Proteína Relacionada com Agouti/metabolismo , Animais , Comportamento Apetitivo/fisiologia , Neurônios GABAérgicos/metabolismo , Habenula/citologia , Região Hipotalâmica Lateral/citologia , Masculino , Camundongos , Modelos Animais , Vias Neurais/fisiologia , Optogenética , Técnicas de Patch-Clamp , Núcleos Septais/citologia , Técnicas Estereotáxicas
19.
Cell Rep ; 27(6): 1650-1656.e4, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31067452

RESUMO

The gustatory system plays an important role in sensing appetitive and aversive tastes for evaluating food quality. In mice, taste signals are relayed by multiple brain regions, including the parabrachial nucleus (PBN) of the pons, before reaching the gustatory cortex via the gustatory thalamus. Recent studies show that taste information at the periphery is encoded in a labeled-line manner, such that each taste modality has its own receptors and neuronal pathway. In contrast, the molecular identity of gustatory neurons in the CNS remains unknown. Here, we show that SatB2-expressing neurons in the PBN play a pivotal role in sweet taste transduction. With cell ablation, in vivo calcium imaging, and optogenetics, we reveal that SatB2PBN neurons encode positive valance and selectively transmit sweet taste signals to the gustatory thalamus.


Assuntos
Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Neurônios/metabolismo , Núcleos Parabraquiais/metabolismo , Paladar , Fatores de Transcrição/metabolismo , Animais , Apetite , Comportamento Animal , Camundongos , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo
20.
PLoS One ; 14(3): e0213552, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30883570

RESUMO

Lactisole, an inhibitor of the human sweet taste receptor, has a 2-phenoxypropionic acid skeleton and has been shown to interact with the transmembrane domain of the T1R3 subunit (T1R3-TMD) of the receptor. Another inhibitor, 2,4-DP, which shares the same molecular skeleton as lactisole, was confirmed to be approximately 10-fold more potent in its inhibitory activity than lactisole; however the structural basis of their inhibitory mechanisms against the receptor remains to be elucidated. Crystal structures of the TMD of metabotropic glutamate receptors, which along with T1Rs are categorized as class C G-protein coupled receptors, have recently been reported and made it possible to create an accurate structural model for T1R3-TMD. In this study, the detailed structural mechanism underlying sweet taste inhibition was characterized by comparing the action of lactisole on T1R3-TMD with that of 2,4-DP. We first performed a series of experiments using cultured cells expressing the sweet taste receptor with mutations and examined the interactions with these inhibitors. Based on the results, we next performed docking simulations and then applied molecular dynamics-based energy minimization. Our analyses clearly revealed that the (S)-isomers of both lactisole and 2,4-DP, interacted with the same seven residues in T1R3-TMD and that the inhibitory potencies of those inhibitors were mainly due to stabilizing interactions mediated via their carboxyl groups in the vertical dimension of the ligand pocket of T1R3-TMD. In addition, 2,4-DP engaged in a hydrophobic interaction mediated by its o-Cl group, and this interaction may be chiefly responsible for the higher inhibitory potency of 2,4-DP.


Assuntos
Derivados de Benzeno/química , Simulação de Dinâmica Molecular , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/química , Cristalografia por Raios X , Células HEK293 , Humanos , Mutação , Domínios Proteicos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-Atividade
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