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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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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. |
format | Online Article Text |
id | pubmed-4485472 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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