help button home button
AJRCMB
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Katsunuma, T.
Right arrow Articles by Mak, J. C. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Katsunuma, T.
Right arrow Articles by Mak, J. C. W.

Am. J. Respir. Cell Mol. Biol., Volume 21, Number 3, September, 1999 409-417

beta 2-Adrenoceptor Agonist-Induced Upregulation of Tachykinin NK2 Receptor Expression and Function in Airway Smooth Muscle

Toshio Katsunuma,* Ad F. Roffel, Carolina R. S. Elzinga, Johan Zaagsma, Peter J. Barnes, and Judith C. W. Mak

Department of Thoracic Medicine, Imperial College School of Medicine, National Heart and Lung Institute, London, United Kingdom; and Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands

Neurokinin A (NKA) induces bronchoconstriction mediated by tachykinin NK2 receptors in animals and humans, and may be increased in asthma. Because beta 2-adrenoceptor agonists are the most widely used bronchodilators in asthma, we investigated the effects of the beta 2-adrenoceptor agonist fenoterol on NK2 receptor messenger RNA (mRNA) and receptor density as well as the functional responses of bovine tracheal smooth muscle to the NK2 receptor agonist [beta -Ala8]-NKA(4-10) in vitro, using Northern blot analysis, receptor binding, and organ bath studies. Incubation with fenoterol induced a time- and concentration-dependent upregulation of NK2 receptor mRNA (71% increase after 12 h at 10-7 M fenoterol), which was abolished by propranolol (a nonselective beta -adrenoceptor agonist) and ICI118551 (a selective beta 2-adrenoceptor antagonist), but not by CGP20712A (a selective beta 1-adrenoceptor antagonist), indicating that fenoterol acts via beta 2-adrenoceptors. These effects were mimicked by forskolin and prostaglandin E2 (PGE2), both agents that increase cyclic adenosine monophosphate (cAMP), and by the cAMP analogue 8-bromo-cAMP. The upregulation was blocked by cycloheximide, indicating that it requires new protein synthesis, and was accompanied by an increase in both the stability of NK2 receptor mRNA and the rate of NK2 receptor gene transcription. Radioligand binding assay using the selective NK2 receptor antagonist [3H]SR48968 showed a significant increase in the number of receptor binding sites after 12 h and 18 h, which was accompanied by an increased contractile responsiveness to the NK2 receptor agonist [beta -Ala8]-NKA(4-10). Dexamethasone completely prevented the fenoterol-induced increase in NK2 receptor mRNA and in the contractile response. We conclude that beta 2-adrenoceptor agonists induce upregulation of functional NK2 receptors in airway smooth muscle by increasing cAMP, and that this can be prevented by a corticosteroid. The increased responsiveness could be relevant to asthma control and mortality.

* Present address: Department of Allergy, National Children's Research Center, 3-35-31, Taishido, Setagaya-ku, Tokyo, 154-8509 Japan




This article has been cited by other articles:


Home page
 Eur Respir JHome page
M. A. Giembycz and R. Newton
Beyond the dogma: novel {beta}2-adrenoceptor signalling in the airways.
Eur. Respir. J., June 1, 2006; 27(6): 1286 - 1306.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
C. Faisy, E. Naline, J.-L. Diehl, X. Emonds-Alt, T. Chinet, and C. Advenier
In vitro sensitization of human bronchus by beta 2-adrenergic agonists
Am J Physiol Lung Cell Mol Physiol, November 1, 2002; 283(5): L1033 - L1042.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
P.J. Barnes
Scientific rationale for inhaled combination therapy with long-acting {beta}2-agonists and corticosteroids
Eur. Respir. J., January 1, 2002; 19(1): 182 - 191.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
J. C. W. Mak, A. F. Roffel, T. Katsunuma, C. R. S. Elzinga, J. Zaagsma, and P. J. Barnes
Up-Regulation of Airway Smooth Muscle Histamine H1 Receptor mRNA, Protein, and Function by beta 2-Adrenoceptor Activation
Mol. Pharmacol., May 1, 2000; 57(5): 857 - 864.
[Abstract] [Full Text]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Crit. Care Med.
Copyright © 1999 American Thoracic Society.