Estrogen effects on human airway smooth muscle involve cAMP and protein kinase A

Elizabeth A. Townsend, Venkatachalem Sathish, Michael A. Thompson, Christina M. Pabelick, Y. S. Prakash

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Clinically observed differences in airway reactivity and asthma exacerbations in women at different life stages suggest a role for sex steroids in modulating airway function although their targets and mechanisms of action are still being explored. We have previously shown that clinically relevant concentrations of exogenous estrogen acutely decrease intracellular calcium ([Ca2+]i) in human airway smooth muscle (ASM), thereby facilitating bronchodilation. In this study, we hypothesized that estrogens modulate cyclic nucleotide regulation, resulting in decreased [Ca2+]i in human ASM. In Fura-2-loaded human ASM cells, 1 nM 17β-estradiol (E2) potentiated the inhibitory effect of the β-adrenoceptor (β-AR) agonist isoproterenol (ISO; 100 nM) on histamine-mediated Ca2+ entry. Inhibition of protein kinase A (PKA) activity (KT5720; 100 nM) attenuated E2 effects on [Ca2+]i. Acute treatment with E2 increased cAMP levels in ASM cells comparable to that of ISO (100 pM). In acetylcholine-contracted airways from female guinea pigs or female humans, E2 potentiated ISO-induced relaxation. These novel data suggest that, in human ASM, physiologically relevant concentrations of estrogens act via estrogen receptors (ERs) and the cAMP pathway to nongenomically reduce [Ca2+]i, thus promoting bronchodilation. Activation of ERs may be a novel adjunct therapeutic avenue in reactive airway diseases in combination with established cAMP-activating therapies such as β2-agonists.

Original languageEnglish (US)
Pages (from-to)L923-L928
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume303
Issue number10
DOIs
StatePublished - Nov 15 2012

Keywords

  • Asthma
  • Bronchial smooth muscle
  • Bronchoconstriction
  • Bronchodilation
  • Calcium
  • Sex steroid
  • β-adrenoceptor

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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