Journal Article

Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction

An, Steven S, McIlmoyle, Elizabeth L, Deshpande, Deepak A, Robinett, Kathryn S, Schillinger, Rachel M, Wang, Wayne C H, Sham, James S K, Liggett, Stephen B

2010

Overview

G protein-coupled receptor (GPCR)-mediated increases in intracellular calcium generally lead to constriction of airway smooth muscle. Deshpande et al . find that bitter taste receptors, another class of GPCRs, are also expressed on airway smooth muscle cells and, once activated, induce a localized increase in intracellular calcium. Paradoxically, this induces relaxation of airway smooth muscle cells via activation of BK Ca channels. These ligands also relax airways in a mouse model of asthma, suggesting they can be used in conjunction with β-adrenergic receptor agonists to treat obstructive lung disease. Bitter taste receptors (TAS2Rs) on the tongue probably evolved to evoke signals for avoiding ingestion of plant toxins. We found expression of TAS2Rs on human airway smooth muscle (ASM) and considered these to be avoidance receptors for inhalants that, when activated, lead to ASM contraction and bronchospasm. TAS2R agonists such as saccharin, chloroquine and denatonium evoked increased intracellular calcium ([Ca 2+ ] i ) in ASM in a Gβγ–, phospholipase Cβ (PLCβ)- and inositol trisphosphate (IP 3 ) receptor–dependent manner, which would be expected to evoke contraction. Paradoxically, bitter tastants caused relaxation of isolated ASM and dilation of airways that was threefold greater than that elicited by β-adrenergic receptor agonists. The relaxation induced by TAS2Rs is associated with a localized [Ca 2+ ] i response at the cell membrane, which opens large-conductance Ca 2+ -activated K + (BK Ca ) channels, leading to ASM membrane hyperpolarization. Inhaled bitter tastants decreased airway obstruction in a mouse model of asthma. Given the need for efficacious bronchodilators for treating obstructive lung diseases, this pathway can be exploited for therapy with the thousands of known synthetic and naturally occurring bitter tastants.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/378/2626/2627 / 631/57/343/1667 / 631/80/86/1999 / 692/699/1785 / Airway obstruction (Medicine) / Airway Obstruction - metabolism / Airway Obstruction - pathology / Airway Obstruction - physiopathology / Animal models in research / Animals / Asthma / Asthma - complications / Asthma - metabolism / Asthma - physiopathology / Biomedical and Life Sciences / Biomedicine / Bronchi - drug effects / Bronchi - metabolism / Bronchi - pathology / Bronchi - physiopathology / Bronchoconstriction - drug effects / Bronchoconstriction - physiology / Calcium / Calcium Signaling - drug effects / Cancer Research / Care and treatment / Cell Separation / Cellular biology / Dose-Response Relationship, Drug / Gene Expression Regulation - drug effects / Genetic aspects / Humans / Infectious Diseases / Ingestion / Large-Conductance Calcium-Activated Potassium Channels - metabolism / Membrane Potentials - drug effects / Membrane Potentials - physiology / Membranes / Metabolic Diseases / Mice / Molecular Medicine / Muscle Relaxation - drug effects / Muscle Relaxation - physiology / Muscle, Smooth - drug effects / Muscle, Smooth - metabolism / Muscle, Smooth - pathology / Muscle, Smooth - physiopathology / Myocytes, Smooth Muscle - metabolism / Myocytes, Smooth Muscle - pathology / Neurosciences / Physiological aspects / Receptors, G-Protein-Coupled - genetics / Receptors, G-Protein-Coupled - metabolism / Respiratory diseases / Risk factors / RNA, Messenger - genetics / RNA, Messenger - metabolism / Saccharin - pharmacology / Signal transduction / Smooth muscle / Taste / Taste - drug effects / Taste - physiology / Taste buds / Taste Receptors, Type 2 / Toxins