Methacholine-induced airway hyperresponsiveness is dependent on Galphaq signaling.
Airway function in health and disease as well as in response to bronchospastic stimuli (i.e., irritants, allergens, and inflammatory mediators) is controlled, in part, by cholinergic muscarinic receptor regulation of smooth muscle. In particular, the dependence of airway smooth muscle contraction/relaxation on heterotrimeric G protein-coupled receptor signaling suggests that these events underlie the responses regulating airway function. Galphaq-containing G proteins are proposed to be a prominent signaling pathway, and the availability of knockout mice deficient of this subunit has allowed for an investigation of its potential role in airway function. Airway responses in Galphaq-deficient mice (activities assessed by both tracheal tension and in vivo lung function measurements) were attenuated relative to wild-type controls. Moreover, ovalbumin sensitization/aerosol challenge of Galphaq-deficient mice also failed to elicit an allergen-induced increase in airway reactivity to methacholine. These findings indicate that cholinergic receptor-mediated responses are dependent on Galphaq-mediated signaling events and identify Galphaq as a potential target of preventative/intervening therapies for lung dysfunction.
Borchers
Michael T
MT
Department of Biochemistry and Molecular Biology, SCJMRB-Research, Mayo Clinic Scottsdale, 13400 E. Shea Blvd., Scottsdale, AZ 85259, USA.
Biechele
T
T
Justice
J P
JP
Ansay
T
T
Cormier
S
S
Mancino
V
V
Wilkie
T M
TM
Simon
M I
MI
Lee
N A
NA
Lee
J J
JJ
D000403:Airway Resistance / Q000502:physiology; D000485:Allergens / Q000494:pharmacology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000503:physiopathology*; D016085:Bronchoconstrictor Agents / Q000494:pharmacology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D016210:Methacholine Chloride / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology; D010047:Ovalbumin / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D014132:Trachea / Q000187:drug effects / Q000503:physiopathology
D000485:Allergens; D016085:Bronchoconstrictor Agents; D016210:Methacholine Chloride; D010047:Ovalbumin; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins