title: Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells.
abstract: 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/intermediate-conductance calcium-activated K(+) 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.
authors.affiliation: Center for Translational Medicine, Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, Pennsylvania; and.
authors.forename: Pawan
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Department of Medicine (Pulmonary Division), University of Maryland, Baltimore, Maryland;
authors.forename: Alfredo
authors.initials: A
authors.lastname: Panebra
authors.affiliation: Center for Translational Medicine, Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, Pennsylvania; and.
authors.forename: Tonio
authors.initials: T
authors.lastname: Pera
authors.affiliation: Center for Translational Medicine, Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, Pennsylvania; and.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Tiegs
authors.affiliation: Department of Medicine (Pulmonary Division), University of Maryland, Baltimore, Maryland;
authors.forename: Alena
authors.initials: A
authors.lastname: Hershfeld
authors.affiliation: Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Kenyon
authors.affiliation: Center for Translational Medicine, Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, Pennsylvania; and deepak.deshpande@jefferson.edu.
authors.forename: Deepak A
authors.initials: DA
authors.lastname: Deshpande
mesh_terms: D001249:Asthma / Q000188:drug therapy / Q000378:metabolism; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D006801:Humans; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D012137:Respiratory System / Q000187:drug effects* / Q000378:metabolism; D013649:Taste / Q000502:physiology
chemical_list: D001993:Bronchodilator Agents; D043562:Receptors, G-Protein-Coupled; C568609:TAS2R1 protein, human; D019869:Phosphatidylinositol 3-Kinases
keywords: G protein-coupled receptor; airway remodeling; asthma; type 2 taste receptors