T. Katsunuma et al., beta(2)-adrenoceptor agonist-induced upregulation of tachykinin NK2 receptor expression and function in airway smooth muscle, AM J RESP C, 21(3), 1999, pp. 409-417
Citations number
36
Categorie Soggetti
da verificare
Journal title
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Neurokinin A (NKA) induces bronchoconstriction mediated by tachykinin NK2 r
eceptors in animals and humans, and may be increased in asthma. Because bet
a(2)-adrenoceptor agonists are the most widely used bronchodilators in asth
ma, we investigated the effects of the beta(2)-adrenoceptor agonist fenoter
ol 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-Ala(8)]-NKA(4-10) in vitro, using Northern blot analysis, rec
eptor binding, and organ bath studies. Incubation with fenoterol induced a
time- and concentration-dependent upregulation of NK2 receptor mRNA (71% in
crease after 12 h at 10(-7) M fenoterol), which was abolished by propranolo
l (a nonselective beta-adrenoceptor agonist) and ICI118551 (a selective bet
a(2)-adrenoceptor antagonist), but not by CGP20712A (a selective beta(1)-ad
renoceptor antagonist), indicating that fenoterol acts via beta(2)-adrenoce
ptors. These effects were mimicked by forskolin and prostaglandin E-2 (PGE,
), both agents that increase cyclic adenosine monophosphate (cAMP), and by
the cAMP analogue 8-bromo-cAMP. The upregulation was blocked by cycloheximi
de, 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 N
K2 receptor gene transcription. Radioligand binding assay using the selecti
ve NK2 receptor antagonist [H-3]SR48968 showed a significant increase in th
e number of receptor binding sites after 12 h and 18 h, which was accompani
ed by an increased contractile responsiveness to the NK2 receptor agonist [
beta-Ala(8)]-NKA(4-10). Dexamethasone completely prevented the fenoterol-in
duced increase in NK2 receptor mRNA and in the contractile response. We con
clude 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 re
levant to asthma control and mortality.