A GABAergic system in airway epithelium is essential for mucus overproduction in asthma.
Gamma-aminobutyric acid (GABA) is an important neurotransmitter that, through the subtype A GABA receptor (GABAAR), induces inhibition in the adult brain. Here we show that an excitatory, rather than inhibitory, GABAergic system exists in airway epithelial cells. Both GABAARs and the GABA synthetic enzyme glutamic acid decarboxylase (GAD) are expressed in pulmonary epithelial cells. Activation of GABAARs depolarized these cells. The expression of GAD in the cytosol and GABAARs in the apical membranes of airway epithelial cells increased markedly when mice were sensitized and then challenged with ovalbumin, an approach for inducing allergic asthmatic reactions. Similarly, GAD and GABAARs in airway epithelial cells of humans with asthma increased after allergen inhalation challenge. Intranasal application of selective GABAAR inhibitors suppressed the hyperplasia of goblet cells and the overproduction of mucus induced by ovalbumin or interleukin-13 in mice. These findings show that a previously unknown epithelial GABAergic system has an essential role in asthma.
Xiang
Yun-Yan
YY
Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
Wang
Shuhe
S
Liu
Mingyao
M
Hirota
Jeremy A
JA
Li
Jingxin
J
Ju
William
W
Fan
Yijun
Y
Kelly
Margaret M
MM
Ye
Bin
B
Orser
Beverley
B
O'Byrne
Paul M
PM
Inman
Mark D
MD
Yang
Xi
X
Lu
Wei-Yang
WY
D000818:Animals; D001249:Asthma / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009093:Mucus / Q000378:metabolism*; D010047:Ovalbumin; D018079:Receptors, GABA / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018079:Receptors, GABA; D005680:gamma-Aminobutyric Acid; D010047:Ovalbumin