title: Pleiotropic Effects of Bitter Taste Receptors on [Ca2+]i Mobilization, Hyperpolarization, and Relaxation of Human Airway Smooth Muscle Cells.
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.
authors.affiliation: Department of Medicine and the Center for Personalized Medicine and Genomics, University of South Florida Morsani College of Medicine, Tampa, FL, United States of America.
authors.forename: Blanca
authors.initials: B
authors.lastname: Camoretti-Mercado
authors.affiliation: Department of Medicine and the Center for Personalized Medicine and Genomics, University of South Florida Morsani College of Medicine, Tampa, FL, United States of America.
authors.forename: Susan H
authors.initials: SH
authors.lastname: Pauer
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America.
authors.forename: Hwan Mee
authors.initials: HM
authors.lastname: Yong
authors.affiliation: Department of Medicine and the Center for Personalized Medicine and Genomics, University of South Florida Morsani College of Medicine, Tampa, FL, United States of America.
authors.forename: Dan'elle C
authors.initials: DC
authors.lastname: Smith
authors.affiliation: Department of Medicine and Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, United States of America.
authors.forename: Deepak A
authors.initials: DA
authors.lastname: Deshpande
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America.
authors.forename: Steven S
authors.initials: SS
authors.lastname: An
authors.affiliation: Department of Medicine and the Center for Personalized Medicine and Genomics, University of South Florida Morsani College of Medicine, Tampa, FL, United States of America; Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, FL, United States of America.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Liggett
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D034341:Aristolochic Acids / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D019332:Endothelin-1 / Q000378:metabolism; D058685:Genetic Pleiotropy; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000166:cytology*; D009126:Muscle Relaxation / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D011968:Receptors, Histamine / Q000378:metabolism; D000098706:Taste Receptors, Type 2
chemical_list: D034341:Aristolochic Acids; D019332:Endothelin-1; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000098706:Taste Receptors, Type 2; D006632:Histamine; D002738:Chloroquine; C000228:aristolochic acid I