Rapid effects of estrogen on intracellular Ca2+ regulation in human airway smooth muscle

Townsend EA, Thompson MA, Pabelick CM, Prakash YS. Rapid effects of estrogen on intracellular Ca2+ regulation in human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 298: L521-L530, 2010. First published January 22, 2010; doi:10.1152/ajplung.00287.2009.-The severity of asthma, a disease characterized by airway hyperresponsiveness and inflammation, is enhanced in some women during the menstrual cycle and during pregnancy but relieved in others. These clinical findings suggest that sex steroids modulate airway tone. Based on well-known relaxant effects of estrogens on vascular smooth muscle, we hypothesized that estrogens relax airway smooth muscle (ASM), thus facilitating bronchodilation. In ASM tissues from female patients, Western and immunocytochemical analyses confirmed the presence of both estrogen receptor (ER) isoforms, ER alpha and ER beta. In fura 2-loaded, dissociated ASM cells maintained in culture, acute exposure to physiological concentrations of 17 beta-estradiol (E-2; 100 pM to 10 nM) decreased the intracellular Ca2+ ([Ca2+](i)) response to 1 mu M histamine, an effect reversed by the ER antagonist ICI-182,780. The ER alpha-selective agonist (R, R)-THC had a greater reducing effect on [Ca2+](i) responses to histamine and 1 mu M ACh compared with the ER beta-selective agonist (DPN). The effects of E-2 on [Ca2+](i) were mediated, at least in part, via decreased Ca2+ influx through L-type channels and store-operated Ca2+ entry but not via Ca2+-activated K+ channels, receptor-operated entry, or sarcoplasmic reticulum reuptake. Overall, these data support our hypothesis that estrogens relax ASM and suggest a potentially novel therapeutic target in airway hyperresponsiveness.