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Pleiotropic Effects of Bitter Taste Receptors on [Ca(2+)](i) Mobilization, Hyperpolarization, and Relaxation of Human Airway Smooth Muscle Cells

Asthma is characterized by airway inflammation and airflow obstruction from human airway smooth muscle (HASM) constriction due to increased local bronchoconstrictive substances. We have recently found bitter taste receptors (TAS2Rs) on HASM, which increase [Ca(2+)](i) and relax the muscle. We report...

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Autores principales: Camoretti-Mercado, Blanca, Pauer, Susan H., Yong, Hwan Mee, Smith, Dan’elle C., Deshpande, Deepak A., An, Steven S., Liggett, Stephen B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485472/
https://www.ncbi.nlm.nih.gov/pubmed/26121686
http://dx.doi.org/10.1371/journal.pone.0131582
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author Camoretti-Mercado, Blanca
Pauer, Susan H.
Yong, Hwan Mee
Smith, Dan’elle C.
Deshpande, Deepak A.
An, Steven S.
Liggett, Stephen B.
author_facet Camoretti-Mercado, Blanca
Pauer, Susan H.
Yong, Hwan Mee
Smith, Dan’elle C.
Deshpande, Deepak A.
An, Steven S.
Liggett, Stephen B.
author_sort Camoretti-Mercado, Blanca
collection PubMed
description Asthma is characterized by airway inflammation and airflow obstruction from human airway smooth muscle (HASM) constriction due to increased local bronchoconstrictive substances. We have recently found bitter taste receptors (TAS2Rs) on HASM, which increase [Ca(2+)](i) and relax the muscle. We report here that some, but not all, TAS2R agonists decrease [Ca(2+)](i) and relax HASM contracted by G-protein coupled receptors (GPCRs) that stimulate [Ca(2+)](i). This suggests both a second pathway by which TAS2Rs relax, and, a heterogeneity of the response phenotype. We utilized eight TAS2R agonists and five procontractile GPCR agonists in cultured HASM cells. We find that heterogeneity in the inhibitory response hinges on which procontractile GPCR is activated. For example, chloroquine inhibits [Ca(2+)](i) increases from histamine, but failed to inhibit [Ca(2+)](i) increases from endothelin-1. Conversely, aristolochic acid inhibited [Ca(2+)](i) increases from endothelin-1 but not histamine. Other dichotomous responses were found when [Ca(2+)](i) was stimulated by bradykinin, angiotensin, and acetylcholine. There was no association between [Ca(2+)](i) inhibition and TAS2R subtype, nor whether [Ca(2+)](i) was increased by G(q)- or G(i)-coupled GPCRs. Selected studies revealed a correlation between [Ca(2+)](i) inhibition and HASM cell-membrane hyperpolarization. To demonstrate physiologic correlates, ferromagnetic beads were attached to HASM cells and cell stiffness measured by magnetic twisting cytometry. Consistent with the [Ca(2+)](i) inhibition results, chloroquine abolished the cell stiffening response (contraction) evoked by histamine but not by endothelin-1, while aristolochic acid inhibited cell stiffening from endothelin-1, but not from histamine. In studies using intact human bronchi, these same differential responses were found. Those TAS2R agonists that decreased [Ca(2+)](i), promoted hyperpolarization, and decreased HASM stiffness, caused relaxation of human airways. Thus TAS2Rs relax HASM in two ways: a low-efficiency de novo [Ca(2+)](i) stimulation, and, a high-efficiency inhibition of GPCR-stimulated [Ca(2+)](i). Furthermore, there is an interaction between TAS2Rs and some GPCRs that facilitates this [Ca(2+)](i) inhibition limb.
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spelling pubmed-44854722015-07-02 Pleiotropic Effects of Bitter Taste Receptors on [Ca(2+)](i) Mobilization, Hyperpolarization, and Relaxation of Human Airway Smooth Muscle Cells Camoretti-Mercado, Blanca Pauer, Susan H. Yong, Hwan Mee Smith, Dan’elle C. Deshpande, Deepak A. An, Steven S. Liggett, Stephen B. PLoS One Research Article Asthma is characterized by airway inflammation and airflow obstruction from human airway smooth muscle (HASM) constriction due to increased local bronchoconstrictive substances. We have recently found bitter taste receptors (TAS2Rs) on HASM, which increase [Ca(2+)](i) and relax the muscle. We report here that some, but not all, TAS2R agonists decrease [Ca(2+)](i) and relax HASM contracted by G-protein coupled receptors (GPCRs) that stimulate [Ca(2+)](i). This suggests both a second pathway by which TAS2Rs relax, and, a heterogeneity of the response phenotype. We utilized eight TAS2R agonists and five procontractile GPCR agonists in cultured HASM cells. We find that heterogeneity in the inhibitory response hinges on which procontractile GPCR is activated. For example, chloroquine inhibits [Ca(2+)](i) increases from histamine, but failed to inhibit [Ca(2+)](i) increases from endothelin-1. Conversely, aristolochic acid inhibited [Ca(2+)](i) increases from endothelin-1 but not histamine. Other dichotomous responses were found when [Ca(2+)](i) was stimulated by bradykinin, angiotensin, and acetylcholine. There was no association between [Ca(2+)](i) inhibition and TAS2R subtype, nor whether [Ca(2+)](i) was increased by G(q)- or G(i)-coupled GPCRs. Selected studies revealed a correlation between [Ca(2+)](i) inhibition and HASM cell-membrane hyperpolarization. To demonstrate physiologic correlates, ferromagnetic beads were attached to HASM cells and cell stiffness measured by magnetic twisting cytometry. Consistent with the [Ca(2+)](i) inhibition results, chloroquine abolished the cell stiffening response (contraction) evoked by histamine but not by endothelin-1, while aristolochic acid inhibited cell stiffening from endothelin-1, but not from histamine. In studies using intact human bronchi, these same differential responses were found. Those TAS2R agonists that decreased [Ca(2+)](i), promoted hyperpolarization, and decreased HASM stiffness, caused relaxation of human airways. Thus TAS2Rs relax HASM in two ways: a low-efficiency de novo [Ca(2+)](i) stimulation, and, a high-efficiency inhibition of GPCR-stimulated [Ca(2+)](i). Furthermore, there is an interaction between TAS2Rs and some GPCRs that facilitates this [Ca(2+)](i) inhibition limb. Public Library of Science 2015-06-29 /pmc/articles/PMC4485472/ /pubmed/26121686 http://dx.doi.org/10.1371/journal.pone.0131582 Text en © 2015 Camoretti-Mercado et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Camoretti-Mercado, Blanca
Pauer, Susan H.
Yong, Hwan Mee
Smith, Dan’elle C.
Deshpande, Deepak A.
An, Steven S.
Liggett, Stephen B.
Pleiotropic Effects of Bitter Taste Receptors on [Ca(2+)](i) Mobilization, Hyperpolarization, and Relaxation of Human Airway Smooth Muscle Cells
title Pleiotropic Effects of Bitter Taste Receptors on [Ca(2+)](i) Mobilization, Hyperpolarization, and Relaxation of Human Airway Smooth Muscle Cells
title_full Pleiotropic Effects of Bitter Taste Receptors on [Ca(2+)](i) Mobilization, Hyperpolarization, and Relaxation of Human Airway Smooth Muscle Cells
title_fullStr Pleiotropic Effects of Bitter Taste Receptors on [Ca(2+)](i) Mobilization, Hyperpolarization, and Relaxation of Human Airway Smooth Muscle Cells
title_full_unstemmed Pleiotropic Effects of Bitter Taste Receptors on [Ca(2+)](i) Mobilization, Hyperpolarization, and Relaxation of Human Airway Smooth Muscle Cells
title_short Pleiotropic Effects of Bitter Taste Receptors on [Ca(2+)](i) Mobilization, Hyperpolarization, and Relaxation of Human Airway Smooth Muscle Cells
title_sort pleiotropic effects of bitter taste receptors on [ca(2+)](i) mobilization, hyperpolarization, and relaxation of human airway smooth muscle cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485472/
https://www.ncbi.nlm.nih.gov/pubmed/26121686
http://dx.doi.org/10.1371/journal.pone.0131582
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