Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction.
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 ([Ca²(+)](i)) in ASM in a Gβγ-, phospholipase Cβ (PLCβ)- and inositol trisphosphate (IP₃) 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 [Ca²(+)](i) response at the cell membrane, which opens large-conductance Ca²(+)-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.
Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Deepak A
DA
Deshpande
Wayne C H
WC
Wang
Elizabeth L
EL
McIlmoyle
Kathryn S
KS
Robinett
Rachel M
RM
Schillinger
Steven S
SS
An
James S K
JS
Sham
Stephen B
SB
Liggett
D000402:Airway Obstruction / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001249:Asthma / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D012439:Saccharin / Q000494:pharmacology; D013649:Taste / Q000187:drug effects / Q000502:physiology*; D000098706:Taste Receptors, Type 2
D051036:Large-Conductance Calcium-Activated Potassium Channels; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D000098706:Taste Receptors, Type 2; D012439:Saccharin