title: Bitter taste receptors in the wrong place: novel airway smooth muscle targets for treating asthma.
abstract: There is a need to expand the classes of drugs used to treat obstructive lung diseases to achieve better outcomes. With only one class of direct bronchodilators (β-agonists), we sought to find receptors on human airway smooth muscle (ASM) that act via a unique mechanism to relax the muscle, have a diverse agonist binding profile to enhance the probability of finding new therapeutics, and relax ASM with equal or greater efficacy than β-agonists. We have found that human and mouse ASM express six bitter taste receptor (TAS2R) subtypes, previously thought only to exist in taste buds of the tongue. Agonists acting at TAS2Rs evoke profound bronchodilation via a Ca(2+)-dependent mechanism. TAS2R function is not altered in asthma models, undergoes minimal tachyphylaxis upon repetitive dosing, and relaxes even under extreme desensitization of relaxation by β-agonists. Taken together, TAS2Rs on ASM represent a novel pathway to consider for development of agonists in the treatment of asthma and chronic obstructive lung disease.
authors.affiliation: Tampa, Florida.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Liggett
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012137:Respiratory System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors; D000098706:Taste Receptors, Type 2
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D018927:Anti-Asthmatic Agents; D001993:Bronchodilator Agents; D043562:Receptors, G-Protein-Coupled; D000098706:Taste Receptors, Type 2