1. Academic Validation
  2. Estrogen receptors differentially regulate intracellular calcium handling in human nonasthmatic and asthmatic airway smooth muscle cells

Estrogen receptors differentially regulate intracellular calcium handling in human nonasthmatic and asthmatic airway smooth muscle cells

  • Am J Physiol Lung Cell Mol Physiol. 2020 Jan 1;318(1):L112-L124. doi: 10.1152/ajplung.00206.2019.
Sangeeta Bhallamudi 1 Jennifer Connell 2 Christina M Pabelick 2 3 Y S Prakash 2 3 Venkatachalem Sathish 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota.
  • 2 Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota.
  • 3 Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
Abstract

Asthma is defined as chronic inflammation of the airways and is characterized by airway remodeling, hyperresponsiveness, and acute bronchoconstriction of airway smooth muscle (ASM) cells. Clinical findings suggest a higher incidence and severity of asthma in adult women, indicating a concrete role of sex Steroids in modulating the airway tone. Estrogen, a major female sex steroid mediates its role through estrogen receptors (ER) ERα and ERβ, which are shown to be expressed in human ASM, and their expression is upregulated in lung inflammation and asthma. Previous studies suggested rapid, nongenomic signaling of estrogen via ERs reduces intracellular calcium ([Ca2+]i), thereby promoting relaxation of ASM. However, long-term ER activation on [Ca2+]i regulation in human ASM during inflammation or in asthma is still not known. In Fura-2-loaded nonasthmatic and asthmatic human ASM cells, we found that prolonged (24 h) exposure to ERα Agonist (PPT) increased [Ca2+]i response to histamine, whereas ERβ activation (WAY) led to decreased [Ca2+] compared with vehicle. This was further confirmed by ER overexpression and knockdown studies using various bronchoconstrictor agents. Interestingly, ERβ activation was more effective than 17β-estradiol in reducing [Ca2+]i responses in the presence of TNF-α or IL-13, while no observable changes were noticed with PPT in the presence of either cytokine. The [Ca2+]i-reducing effects of ERβ were mediated partially via L-type Calcium Channel inhibition and increased Ca2+ sequestration by sarcoplasmic reticulum. Overall, these data highlight the differential signaling of ERα and ERβ in ASM during inflammation. Specific ERβ activation reduces [Ca2+]i in the inflamed ASM cells and is likely to play a crucial role in regulating ASM contractility, thereby relaxing airways.

Keywords

asthma; calcium; estrogen; inflammation; sex steroid; signaling.

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