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Updated: Nov 28, 2025
In vitro Measurements of Tracheal Constriction Using Mice
Published on: June 25, 2012
FFAR1 activation attenuates histamine-induced myosin light chain phosphorylation and cortical tension development in
Shengjie Xu1,2, Anthony Schwab2, Nikhil Karmacharya2
1The Joint Graduate Program in Toxicology, Department of Pharmacology & Toxicology, Ernest Mario School of Pharmacy, Piscataway, USA.
Background:
Activation of free fatty acid receptors (FFAR1 and FFAR4) which are G protein-coupled receptors (GPCRs) with established (patho)physiological roles in a variety of obesity-related disorders, induce human airway smooth muscle (HASM) cell proliferation and shortening. We reported amplified agonist-induced cell shortening in HASM cells obtained from obese lung donors. We hypothesized that FFAR1 modulate excitation-contraction (EC) coupling in HASM cells and play a role in obesity-associated airway hyperresponsiveness.
Methods:
In HASM cells pre-treated (30 min) with FFAR1 agonists TAK875 and GW9508, we measured histamine-induced Ca2+ mobilization, myosin light chain (MLC) phosphorylation, and cortical tension development with magnetic twisting cytometry (MTC). Phosphorylation of MLC phosphatase and Akt also were determined in the presence of the FFAR1 agonists or vehicle. In addition, the effects of TAK875 on MLC phosphorylation were measured in HASM cells desensitized to β2AR agonists by overnight salmeterol treatment. The inhibitory effect of TAK875 on MLC phosphorylation was compared between HASM cells from age and sex-matched non-obese and obese human lung donors. The mean measurements were compared using One-Way ANOVA with Dunnett's test for multiple group comparisons or Student's t-test two-group comparison. For cortical tension measurements by magnetic twisted cytometry, mixed effect model using SAS V.9.2 was applied. Means were considered significant when p ≤ 0.05.
Results:
Unexpectedly, we found that TAK875, a synthetic FFAR1 agonist, attenuated histamine-induced MLC phosphorylation and cortical tension development in HASM cells. These physiological outcomes were unassociated with changes in histamine-evoked Ca2+ flux, protein kinase B (AKT) activation, or MLC phosphatase inhibition. Of note, TAK875-mediated inhibition of MLC phosphorylation was maintained in β2AR-desensitized HASM cells and across obese and non-obese donor-derived HASM cells.
Conclusions:
Taken together, our findings identified the FFAR1 agonist TAK875 as a novel bronchoprotective agent that warrants further investigation to treat difficult-to-control asthma and/or airway hyperreactivity in obesity.
Insights
The free fatty acid receptor 1 (FFAR1) agonist TAK875 unexpectedly reduced airway smooth muscle contraction and myosin light chain phosphorylation. This suggests TAK875 may be a novel treatment for asthma and obesity-related airway hyperresponsiveness.
Area of Science:
- Cellular biology
- Pharmacology
- Respiratory medicine
Background:
- Free fatty acid receptors (FFAR1 and FFAR4) are GPCRs involved in obesity-related disorders.
- FFAR1 activation can increase human airway smooth muscle (HASM) cell proliferation and shortening.
- Obese individuals exhibit amplified agonist-induced HASM cell shortening.
Purpose of the Study:
- To investigate the role of FFAR1 in excitation-contraction (EC) coupling in HASM cells.
- To determine if FFAR1 plays a role in obesity-associated airway hyperresponsiveness.
Main Methods:
- HASM cells were treated with FFAR1 agonists (TAK875, GW9508).
- Measurements included histamine-induced Ca2+ mobilization, MLC phosphorylation, and cortical tension (MTC).
- Effects were assessed in β2AR-desensitized cells and cells from obese/non-obese donors.
Main Results:
- TAK875 unexpectedly attenuated histamine-induced MLC phosphorylation and cortical tension.
- These effects were independent of Ca2+ flux, AKT activation, or MLC phosphatase inhibition.
- TAK875's inhibitory effect was consistent in β2AR-desensitized and obese/non-obese donor cells.
Conclusions:
- FFAR1 agonist TAK875 demonstrates novel bronchoprotective properties.
- TAK875 warrants further investigation for treating difficult asthma and obesity-related airway hyperreactivity.
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