Solitary chemosensory cells in the respiratory and vomeronasal epithelium of the human nose: a pilot study

Background: Recently, solitary chemosensory cells have been described in the respiratory and vomeronasal epithelium of the rodent nose. Expressing G-protein coupled receptors for sweet, umami and bitter taste transduction, these cells are thought to mediate trigeminal reflexes upon stimulation with chemical irritants. The present study analyzes human nasal mucosa for the presence of solitary chemosensory cells. Methodology: In human tissue samples from respiratory mucosa and the vomeronasal organ, gene expression of taste receptors families was studied in five patients using the Affymetrix Human Gene 1.0 ST Array and immunohistochemistry with specific antibodies. Results: Immunohistochemistry revealed that solitary chemosensory cells expressing G-protein coupled receptors for sweet, umami and bitter taste transduction are present in the human nose. cDNA microarray analysis congruently showed that cells expressing bitter taste receptors accumulate in the vomeronasal organ compared to the respiratory epithelium. Conclusions: Solitary chemosensory cells expressing taste receptors are also present in the human nose. Since they are thought to mediate trigeminal reflexes, their role in the pathogenesis of nasal hyperreagibility should be elucidated in further studies.

Download Full-text

Beyond the Flavour: The Potential Druggability of Chemosensory G Protein-Coupled Receptors

International Journal of Molecular Sciences ◽

10.3390/ijms20061402 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1402 ◽

Cited By ~ 15

Author(s):

Antonella Di Pizio ◽

Maik Behrens ◽

Dietmar Krautwurst

Keyword(s):

G Protein ◽

Drug Targets ◽

Current Knowledge ◽

Chemical Space ◽

G Protein Coupled Receptors ◽

The Body ◽

Odorant Receptors ◽

Taste Receptors ◽

Umami Taste ◽

G Protein Coupled

G protein-coupled receptors (GPCRs) belong to the largest class of drug targets. Approximately half of the members of the human GPCR superfamily are chemosensory receptors, including odorant receptors (ORs), trace amine-associated receptors (TAARs), bitter taste receptors (TAS2Rs), sweet and umami taste receptors (TAS1Rs). Interestingly, these chemosensory GPCRs (csGPCRs) are expressed in several tissues of the body where they are supposed to play a role in biological functions other than chemosensation. Despite their abundance and physiological/pathological relevance, the druggability of csGPCRs has been suggested but not fully characterized. Here, we aim to explore the potential of targeting csGPCRs to treat diseases by reviewing the current knowledge of csGPCRs expressed throughout the body and by analysing the chemical space and the drug-likeness of flavour molecules.

Download Full-text

G Protein-Coupled Receptors in Taste Physiology and Pharmacology

Frontiers in Pharmacology ◽

10.3389/fphar.2020.587664 ◽

2020 ◽

Vol 11 ◽

Author(s):

Raise Ahmad ◽

Julie E. Dalziel

Keyword(s):

Binding Site ◽

G Protein ◽

Molecular Mechanisms ◽

Taste Receptor ◽

Receptor Activation ◽

G Protein Coupled Receptors ◽

Type I ◽

Taste Receptors ◽

Agonist Binding ◽

G Protein Coupled

Heterotrimeric G protein-coupled receptors (GPCRs) comprise the largest receptor family in mammals and are responsible for the regulation of most physiological functions. Besides mediating the sensory modalities of olfaction and vision, GPCRs also transduce signals for three basic taste qualities of sweet, umami (savory taste), and bitter, as well as the flavor sensation kokumi. Taste GPCRs reside in specialised taste receptor cells (TRCs) within taste buds. Type I taste GPCRs (TAS1R) form heterodimeric complexes that function as sweet (TAS1R2/TAS1R3) or umami (TAS1R1/TAS1R3) taste receptors, whereas Type II are monomeric bitter taste receptors or kokumi/calcium-sensing receptors. Sweet, umami and kokumi receptors share structural similarities in containing multiple agonist binding sites with pronounced selectivity while most bitter receptors contain a single binding site that is broadly tuned to a diverse array of bitter ligands in a non-selective manner. Tastant binding to the receptor activates downstream secondary messenger pathways leading to depolarization and increased intracellular calcium in TRCs, that in turn innervate the gustatory cortex in the brain. Despite recent advances in our understanding of the relationship between agonist binding and the conformational changes required for receptor activation, several major challenges and questions remain in taste GPCR biology that are discussed in the present review. In recent years, intensive integrative approaches combining heterologous expression, mutagenesis and homology modeling have together provided insight regarding agonist binding site locations and molecular mechanisms of orthosteric and allosteric modulation. In addition, studies based on transgenic mice, utilizing either global or conditional knock out strategies have provided insights to taste receptor signal transduction mechanisms and their roles in physiology. However, the need for more functional studies in a physiological context is apparent and would be enhanced by a crystallized structure of taste receptors for a more complete picture of their pharmacological mechanisms.

Download Full-text

Natural Compounds as Guides for the Discovery of Drugs Targeting G-Protein-Coupled Receptors

Molecules ◽

10.3390/molecules25215060 ◽

2020 ◽

Vol 25 (21) ◽

pp. 5060

Author(s):

Joan Serrano-Marín ◽

Irene Reyes-Resina ◽

Eva Martínez-Pinilla ◽

Gemma Navarro ◽

Rafael Franco

Keyword(s):

Natural Products ◽

Drug Discovery ◽

G Protein ◽

Natural Compounds ◽

G Protein Coupled Receptors ◽

Taste Receptors ◽

Allosteric Modulators ◽

Chemical Structures ◽

Therapeutic Drugs ◽

G Protein Coupled

G protein-coupled receptors (GPCRs), which constitute the most populous family of the human proteome, are the target of 35–45% of approved therapeutic drugs. This review focuses on natural products (excluding peptides) that target GPCRs. Natural compounds identified so far as agonists, antagonists or allosteric modulators of GPCRs have been found in all groups of existing living beings according to Whittaker’s Five Kingdom Classification, i.e., bacteria (monera), fungi, protoctists, plants and animals. Terpenoids, alkaloids and flavonoids are the most common chemical structures that target GPCRs whose endogenous ligands range from lipids to epinephrine, from molecules that activate taste receptors to molecules that activate smell receptors. Virtually all of the compounds whose formula is displayed in this review are pharmacophores with potential for drug discovery; furthermore, they are expected to help expand the number of GPCRs that can be considered as therapeutic targets.

Download Full-text

BitterMatch: Recommendation systems for matching molecules with bitter taste receptors

10.1101/2022.01.13.476205 ◽

2022 ◽

Author(s):

Eitan Margulis ◽

Yuli Slavutsky ◽

Tatjana Lang ◽

Mike Behrens ◽

Yuval Benjamini ◽

...

Keyword(s):

Experimental Data ◽

Bitter Taste ◽

Recommendation Systems ◽

G Protein Coupled Receptors ◽

Taste Receptors ◽

Drug Compliance ◽

G Protein Coupled ◽

Hybrid Recommendation

Bitterness is an aversive cue elicited by thousands of chemically diverse compounds. Bitter taste may prevent consumption of foods and jeopardize drug compliance. The G protein-coupled receptors for bitter taste, TAS2Rs, have species-dependent number of subtypes and varying expression levels in extraoral tissues. Molecular recognition by TAS2R subtypes is physiologically important, and presents a challenging case study for ligand-receptor matchmaking. Inspired by hybrid recommendation systems, we developed a new set of similarity features, and created the BitterMatch algorithm that predicts associations of ligands to receptors with ~80% precision at ~50% recall. Associations for several compounds were tested in-vitro, resulting in 80% precision and 42% recall. The encouraging performance was achieved by including receptor properties and integrating experimentally determined ligand-receptor associations with chemical ligand-to-ligand similarities. BitterMatch can predict off-targets for bitter drugs, identify novel ligands and guide flavor design. Inclusion of neighbor-informed similarities improves as experimental data mounts, and provides a generalizable framework for molecule-biotarget matching.

Download Full-text

Extraoral bitter taste receptors in health and disease

The Journal of General Physiology ◽

10.1085/jgp.201611637 ◽

2017 ◽

Vol 149 (2) ◽

pp. 181-197 ◽

Cited By ~ 75

Author(s):

Ping Lu ◽

Cheng-Hai Zhang ◽

Lawrence M. Lifshitz ◽

Ronghua ZhuGe

Keyword(s):

Innate Immunity ◽

Bitter Taste ◽

G Protein Coupled Receptors ◽

The Body ◽

Taste Perception ◽

Taste Receptors ◽

Human Disorders ◽

Health And Disease ◽

Bitter Taste Receptors ◽

G Protein Coupled

Bitter taste receptors (TAS2Rs or T2Rs) belong to the superfamily of seven-transmembrane G protein–coupled receptors, which are the targets of >50% of drugs currently on the market. Canonically, T2Rs are located in taste buds of the tongue, where they initiate bitter taste perception. However, accumulating evidence indicates that T2Rs are widely expressed throughout the body and mediate diverse nontasting roles through various specialized mechanisms. It has also become apparent that T2Rs and their polymorphisms are associated with human disorders. In this review, we summarize the physiological and pathophysiological roles that extraoral T2Rs play in processes as diverse as innate immunity and reproduction, and the major challenges in this emerging field.

Download Full-text

Functional Microswitches of Mammalian G Protein-Coupled Bitter-Taste Receptors

10.1101/2020.10.23.348706 ◽

2020 ◽

Author(s):

Jérémie Topin ◽

Cédric Bouysset ◽

Yiseul Kim ◽

MeeRa Rhyu ◽

Sébastien Fiorucci ◽

...

Keyword(s):

G Protein ◽

Bitter Taste ◽

Current Knowledge ◽

Receptor Activation ◽

Amino Acid Sequences ◽

Site Directed Mutagenesis ◽

Taste Receptors ◽

Bitter Taste Receptors ◽

G Protein Coupled

AbstractBitter taste receptors (TAS2Rs) are a poorly understood subgroup of G protein-coupled receptors (GPCR). No experimental structure of these receptors is available and key-residues controlling their function remain mostly unknown. Here, we have identified the functional microswitches that encode agonist sensing and downstream signaling mechanisms within TAS2Rs sequences. We thoroughly re-aligned the amino-acid sequences of the 25 human TAS2Rs considering residue conservations and all the experimental data from the literature as constraints. As a test case, an accurate homology model of TAS2R16 was constructed and examined by site-directed mutagenesis and in vitro functional assays. Conserved motifs acting as microswitches during agonist-sensing and receptor activation were pinpointed by comparison with the current knowledge on class A GPCRs. Unravelling these sequence – function relationships is of utmost importance to streamline how TAS2Rs functions are encrypted in their sequence.

Download Full-text