The Pharmacology and Signaling of Bitter, Sweet, and Umami Taste Sensing

Palmer, R. Kyle

doi:10.1124/mi.7.2.9

Cited by 64 publications

(51 citation statements)

References 111 publications

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“…Chloroquine and quinine demonstrated a different level of inhibition of growth factor-induced gene expression in ASM cells presumably because of differences in the activation of signaling by different subtypes of TAS2Rs. We also recognize that these studies do not address signaling via any specific subtype of TAS2R because of a lack of (41) and therefore require micromolar concentrations of the agonists to activate these receptors. Similar ranges of concentrations are reported in studies using heterologous expression models as well (35).…”

Section: Discussionmentioning

confidence: 99%

Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells

Sharma

Panebra

Pera

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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-Airway remodeling is a hallmark feature of asthma and chronic obstructive pulmonary disease. Clinical studies and animal models have demonstrated increased airway smooth muscle (ASM) mass, and ASM thickness is correlated with severity of the disease. Current medications control inflammation and reverse airway obstruction effectively but have limited effect on remodeling. Recently we identified the expression of bitter taste receptors (TAS2R) on ASM cells, and activation with known TAS2R agonists resulted in ASM relaxation and bronchodilation. These studies suggest that TAS2R can be used as new therapeutic targets in the treatment of obstructive lung diseases. To further establish their effectiveness, in this study we aimed to determine the effects of TAS2R agonists on ASM growth and promitogenic signaling. Pretreatment of healthy and asthmatic human ASM cells with TAS2R agonists resulted in a dose-dependent inhibition of ASM proliferation. The antimitogenic effect of TAS2R ligands was not dependent on activation of protein kinase A, protein kinase C, or high/intermediateconductance calcium-activated K ϩ channels. Immunoblot analyses revealed that TAS2R agonists inhibit growth factor-activated protein kinase B phosphorylation without affecting the availability of phosphatidylinositol 3,4,5-trisphosphate, suggesting TAS2R agonists block signaling downstream of phosphatidylinositol 3-kinase. Furthermore, the antimitogenic effect of TAS2R agonists involved inhibition of induced transcription factors (activator protein-1, signal transducer and activator of transcription-3, E2 factor, nuclear factor of activated T cells) and inhibition of expression of multiple cell cycle regulatory genes, suggesting a direct inhibition of cell cycle progression. Collectively, these findings establish the antimitogenic effect of TAS2R agonists and identify a novel class of receptors and signaling pathways that can be targeted to reduce or prevent airway remodeling as well as bronchoconstriction in obstructive airway disease. asthma; airway remodeling; G protein-coupled receptor; type 2 taste receptors G PROTEIN-COUPLED RECEPTOR (GPCR) signaling plays a vital role in the regulation of airway smooth muscle (ASM) contraction, relaxation, and proliferation (4, 12). Exaggerated presentation of procontractile GPCR agonists in the airways during allergic inflammation contributes to bronchoconstriction in obstructive airway disease such as asthma. Another salient feature of inflammatory airway diseases is airway remodeling that is characterized by excessive proliferation and accumulation of resident cells, including ASM cells. Animal models demonstrate ASM mass is increased by allergic airway inflammation, while human studies demonstrate a progressive increase in ASM mass in asthmatic subjects that increases both dynamic and fixed airway resistance, limiting the effectiveness of current rescue bronchodilators (11,21,22,26). Current antiasthma therapies, including ␤-agonists and corticosteroids, aim at alleviating bronchoconstriction and infl...

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Section: Discussionmentioning

confidence: 99%

Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells

Sharma

Panebra

Pera

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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show abstract

“…In fact, in the search for taste additives, companies that specialize in 66 URWYLER the development of such chemicals proceed in much the same way that pharmaceutical companies do when pursuing a new target [for example by expressing the receptors of interest in recombinant cell lines (Ozeck et al, 2004) and using these for HTS of large compound libraries (Palmer, 2007;Zhang et al, 2008a)]. The potencies of such molecules obtained in these in vitro assays can be expected to reliably predict their in vivo activity, because no biological barriers oppose them and no pharmacokinetic considerations apply.…”

Section: A Taste-more Than Just a Pleasurementioning

confidence: 99%

“…Whereas beforehand the characterization of tastant molecules relied essentially on behavioral measures (Palmer, 2007), the relatively recent discovery and characterization of taste receptors (see section II.B) made the area of taste research amenable to the concepts and techniques of molecular pharmacology. In fact, in the search for taste additives, companies that specialize in 66 URWYLER the development of such chemicals proceed in much the same way that pharmaceutical companies do when pursuing a new target [for example by expressing the receptors of interest in recombinant cell lines (Ozeck et al, 2004) and using these for HTS of large compound libraries (Palmer, 2007;Zhang et al, 2008a)].…”

Section: A Taste-more Than Just a Pleasurementioning

confidence: 99%

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

2011

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“…Loss of TRPV channel function does not restore grk-2 response to other ASH-detected stimuli: Loss of OSM-9 or OCR-2 TRPV function in grk-2 mutant animals restored response to soluble bitter compounds that likely act through G protein-coupled receptors (Chandrashekar et al 2006;Palmer 2007) expressed in the ASH sensory neurons. Olfactory receptors are also G protein-coupled receptors (Dryer and Berghard 1999) and grk-2 animals are severely defective in their response to the aversive odorant octanol .…”

Section: Resultsmentioning

confidence: 99%

“…Olfaction and gustatory responses to bitter, sweet, and umami stimuli are generally mediated by G protein-coupled signal transduction pathways that are conserved across species (Dryer and Berghard 1999;Chandrashekar et al 2006;Palmer 2007). Signaling is initiated when a ligand (odorant or tastant) binds to a seven-transmembrane G protein-coupled receptor (GPCR), inducing a conformational change in the receptor that activates the associated heterotrimeric G proteins.…”

mentioning

confidence: 99%

Caenorhabditis elegans TRPV Channels Function in a Modality-Specific Pathway to Regulate Response to Aberrant Sensory Signaling

Ezak

Hong²,

Ferkey

2010

Genetics

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Olfaction and some forms of taste (including bitter) are mediated by G protein-coupled signal transduction pathways. Olfactory and gustatory ligands bind to chemosensory G protein-coupled receptors (GPCRs) in specialized sensory cells to activate intracellular signal transduction cascades. G protein-coupled receptor kinases (GRKs) are negative regulators of signaling that specifically phosphorylate activated GPCRs to terminate signaling. Although loss of GRK function usually results in enhanced cellular signaling, Caenorhabditis elegans lacking GRK-2 function are not hypersensitive to chemosensory stimuli. Instead, grk-2 mutant animals do not chemotax toward attractive olfactory stimuli or avoid aversive tastes and smells. We show here that loss-offunction mutations in the transient receptor potential vanilloid (TRPV) channels OSM-9 and OCR-2 selectively restore grk-2 behavioral avoidance of bitter tastants, revealing modality-specific mechanisms for TRPV channel function in the regulation of C. elegans chemosensation. Additionally, a single amino acid point mutation in OCR-2 that disrupts TRPV channel-mediated gene expression, but does not decrease channel function in chemosensory primary signal transduction, also restores grk-2 bitter taste avoidance. Thus, loss of GRK-2 function may lead to changes in gene expression, via OSM-9/OCR-2, to selectively alter the levels of signaling components that transduce or regulate bitter taste responses. Our results suggest a novel mechanism and multiple modality-specific pathways that sensory cells employ in response to aberrant signal transduction.

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The Pharmacology and Signaling of Bitter, Sweet, and Umami Taste Sensing

Cited by 64 publications

References 111 publications

Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells

Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

Caenorhabditis elegans TRPV Channels Function in a Modality-Specific Pathway to Regulate Response to Aberrant Sensory Signaling

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