Pleiotropic Effects of Bitter Taste Receptors on [Ca2+]i Mobilization, Hyperpolarization, and Relaxation of Human Airway Smooth Muscle Cells.

Authors

Blanca Camoretti-Mercado, Department of Medicine, Center for Personalized Medicine and Genomics, University of South Florida Morsani College of Medicine
Susan H Pauer, Department of Medicine, Center for Personalized Medicine and Genomics, University of South Florida Morsani College of Medicine
Hwan Mee Yong, Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health
Dan'elle C Smith, Department of Medicine, Center for Personalized Medicine and Genomics, University of South Florida Morsani College of Medicine
Deepak A. Deshpande, PhD, Center for Translational Medicine, Department of Medicine, Thomas Jefferson UniversityFollow
Steven S An, Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public HealthFollow
Stephen B Liggett, Department of Medicine, Center for Personalized Medicine and Genomics, University of South Florida Morsani College of Medicine; Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine

Document Type

Article

Publication Date

6-29-2015

Comments

This article has been peer reviewed. It was published in: PLoS ONE.

Volume 10, Issue 6, 29 June 2015, Article number e0131582.

The published version is available at DOI: 10.1371/journal.pone.0131582

Copyright © 2015 Camoretti-Mercado et al

Abstract

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 [Ca2+]i and relax the muscle. We report here that some, but not all, TAS2R agonists decrease [Ca2+]i and relax HASM contracted by G-protein coupled receptors (GPCRs) that stimulate [Ca2+]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 [Ca2+]i increases from histamine, but failed to inhibit [Ca2+]i increases from endothelin-1. Conversely, aristolochic acid inhibited [Ca2+]i increases from endothelin-1 but not histamine. Other dichotomous responses were found when [Ca2+]i was stimulated by bradykinin, angiotensin, and acetylcholine. There was no association between [Ca2+]i inhibition and TAS2R subtype, nor whether [Ca2+]i was increased by Gq- or Gi-coupled GPCRs. Selected studies revealed a correlation between [Ca2+]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 [Ca2+]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 [Ca2+]i, promoted hyperpolarization, and decreased HASM stiffness, caused relaxation of human airways. Thus TAS2Rs relax HASM in two ways: a low-efficiency de novo [Ca2+]i stimulation, and, a high-efficiency inhibition of GPCR-stimulated [Ca2+]i. Furthermore, there is an interaction between TAS2Rs and some GPCRs that facilitates this [Ca2+]i inhibition limb.

Recommended Citation

Camoretti-Mercado, Blanca; Pauer, Susan H; Yong, Hwan Mee; Smith, Dan'elle C; Deshpande, PhD, Deepak A.; An, Steven S; and Liggett, Stephen B, "Pleiotropic Effects of Bitter Taste Receptors on [Ca2+]i Mobilization, Hyperpolarization, and Relaxation of Human Airway Smooth Muscle Cells." (2015). Center for Translational Medicine Faculty Papers. Paper 33.
https://jdc.jefferson.edu/transmedfp/33

PubMed ID

26121686