Androgen receptor-mediated regulation of intracellular calcium in human airway smooth muscle cells

Background/Aims: With the prevalence of asthma being greater in women, detrimental effects of female sex steroids have been explored, but potential protective effects of androgens are not established. Airway smooth muscle (ASM) is a key cell type in contractility and remodelling of asthma. There are no data on expression and functionality of androgen receptor (AR) in human ASM cells. Methods: We used primary human ASM cells from non-asthmatics vs. asthmatics to determine AR expression at baseline and with inflammation measured using Western blotting/qRT-PCR, and the role of AR in regulating intracellular Ca²⁺ ([Ca²⁺]_i) measured using Fluo-3 loaded real time [Ca²⁺]_i imaging. Results: We found that compared to females, baseline AR is greater in male ASM and increases with inflammation/asthma. Androgens, via AR, blunted TNFα or IL-13-induced enhancement of ASM [Ca²⁺]_i in both males and females, with retained efficacy in asthmatics. AR effects involve reduced Ca²⁺ influx via L-type channels and store-operated Ca²⁺ entry, the latter by downregulating STIM1 and Orai1 and increasing TMEM66. Conclusion: Our data show AR expression is increased in female ASM with asthma, but has retained functionality that could be used to reduce [Ca²⁺]_i towards alleviating airway hyperresponsiveness.