Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
Contributed by Lily Yeh Jan, August 23, 2012 (sent for review June 1, 2012)
Abstract
Mucous cell hyperplasia and airway smooth muscle (ASM) hyperresponsiveness are hallmark features of inflammatory airway diseases, including asthma. Here, we show that the recently identified calcium-activated chloride channel (CaCC) TMEM16A is expressed in the adult airway surface epithelium and ASM. The epithelial expression is increased in asthmatics, particularly in secretory cells. Based on this and the proposed functions of CaCC, we hypothesized that TMEM16A inhibitors would negatively regulate both epithelial mucin secretion and ASM contraction. We used a high-throughput screen to identify small-molecule blockers of TMEM16A-CaCC channels. We show that inhibition of TMEM16A-CaCC significantly impairs mucus secretion in primary human airway surface epithelial cells. Furthermore, inhibition of TMEM16A-CaCC significantly reduces mouse and human ASM contraction in response to cholinergic agonists. TMEM16A-CaCC blockers, including those identified here, may positively impact multiple causes of asthma symptoms.
Footnotes
- ↵1To whom correspondence may be addressed. E-mail: jason.rock{at}ucsf.edu or lily.jan{at}ucsf.edu.
Author contributions: F.H., H.Z., M.W., H.Y., M.K., C.J.P., P.G.W., O.D.S., X.H., D.S., J.V.F., W.F., M.L., Y.-N.J., L.Y.J., and J.R.R. designed research; F.H., H.Z., M.W., H.Y., M.K., C.J.P., P.G.W., O.D.S., M.L.D., X.H., J.V.F., M.L., Y.-N.J., L.Y.J., and J.R.R. performed research; F.H., H.Z., M.W., H.Y., P.G.W., O.D.S., X.H., J.V.F., P.J.W., B.L.M.H., W.F., M.L., Y.-N.J., L.Y.J., and J.R.R. contributed new reagents/analytic tools; F.H., H.Z., M.W., H.Y., M.K., C.J.P., P.G.W., O.D.S., M.L.D., X.H., D.S., J.V.F., M.L., Y.-N.J., L.Y.J., and J.R.R. analyzed data; and F.H., C.J.P., Y.-N.J., L.Y.J., and J.R.R. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1214596109/-/DCSupplemental.
TMEM16A in asthma
Sign up for Article Alerts
Jump to section
You May Also be Interested in
Did the Caribbean sweep into the western Amazon millions of years ago, shaping the region’s rich biodiversity?
Image credit: Tacio Cordeiro Bicudo (University of São Paulo, São Paulo, Brazil), Victor Sacek (University of São Paulo, São Paulo, Brazil), and Lucy Reading-Ikkanda (artist).
Settlements 4,200 years ago may have suffered from overpopulation before drought and lower temperatures ultimately made them unsustainable.
Image credit: Andrea Ricci.
Mara Reed and Michael Manga explore why Yellowstone's Steamboat Geyser resumed erupting in 2018.
Some songbird parents might improve their own fitness by manipulating their offspring into leaving the nest early, at the cost of fledgling survival, a study finds.
Image credit: Gil Eckrich (photographer).