TAS2R activation promotes airway smooth muscle relaxation despite β(2)-adrenergic receptor tachyphylaxis.
Recently, bitter taste receptors (TAS2Rs) were found in the lung and act to relax airway smooth muscle (ASM) via intracellular Ca(2+) concentration signaling generated from restricted phospholipase C activation. As potential therapy, TAS2R agonists could be add-on treatment when patients fail to achieve adequate bronchodilation with chronic β-agonists. The β(2)-adrenergic receptor (β(2)AR) of ASM undergoes extensive functional desensitization. It remains unknown whether this desensitization affects TAS2R function, by cross talk at the receptors or distal common components in the relaxation machinery. We studied intracellular signaling and cell mechanics using isolated human ASM, mouse tracheal responses, and human bronchial responses to characterize TAS2R relaxation in the context of β(2)AR desensitization. In isolated human ASM, magnetic twisting cytometry revealed >90% loss of isoproterenol-promoted decrease in cell stiffness after 18-h exposure to albuterol. Under these same conditions of β(2)AR desensitization, the TAS2R agonist chloroquine relaxation response was unaffected. TAS2R-mediated stimulation of intracellular Ca(2+) concentration in human ASM was unaltered by albuterol pretreatment, in contrast to cAMP signaling, which was desensitized by >90%. In mouse trachea, β(2)AR desensitization by β-agonist amounted to 92 ± 6.0% (P < 0.001), while, under these same conditions, TAS2R desensitization was not significant (11 ± 3.5%). In human lung slices, chronic β-agonist exposure culminated in 64 ± 5.7% (P < 0.001) desensitization of β(2)AR-mediated dilation of carbachol-constricted airways that was reversed by chloroquine. We conclude that there is no evidence for physiologically relevant cross-desensitization of TAS2R-mediated ASM relaxation from chronic β-agonist treatment. These findings portend a favorable therapeutic profile for TAS2R agonists for the treatment of bronchospasm in asthma or chronic obstructive lung disease.
Program in Respiratory Biology and Lung Disease, Johns Hopkins University, Bloomberg School of Public Health, 615 N Wolfe St., Rm. E-7616, Baltimore, MD 21205, USA. san@jhsph.edu
Steven S
SS
An
Wayne C H
WC
Wang
Cynthia J
CJ
Koziol-White
Kwangmi
K
Ahn
Danielle Y
DY
Lee
Richard C
RC
Kurten
Reynold A
RA
Panettieri
Stephen B
SB
Liggett
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D002738:Chloroquine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D012143:Respiratory Physiological Phenomena / Q000187:drug effects; D012137:Respiratory System / Q000187:drug effects / Q000378:metabolism*; D013618:Tachyphylaxis / Q000502:physiology*; D000098706:Taste Receptors, Type 2
D000318:Adrenergic beta-Agonists; D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled; D000098706:Taste Receptors, Type 2; D016210:Methacholine Chloride; D002738:Chloroquine; D007545:Isoproterenol; D000420:Albuterol