Tas2R activation relaxes airway smooth muscle by release of Gαt targeting on AChR signaling.

Abstract

Both chronic obstructive pulmonary disease (COPD) and asthma are severe respiratory diseases. Bitter receptor-mediated bronchodilation is a potential therapy for asthma, but the mechanism underlying the agonistic relaxation of airway smooth muscle (ASM) is not well defined. By exploring the ASM relaxation mechanism of bitter substances, we observed that pretreatment with the bitter substances nearly abolished the methacholine (MCh)-induced increase in the ASM cell (ASMC) calcium concentration, thereby suppressing the calcium-induced contraction release. The ASM relaxation was significantly inhibited by simultaneous deletion of three Gαt proteins, suggesting an interaction between Tas2R and AChR signaling cascades in the relaxation process. Biochemically, the Gαt released by Tas2R activation complexes with AChR and blocks the Gαq cycling of AChR signal transduction. More importantly, a bitter substance, kudinoside A, not only attenuates airway constriction but also significantly inhibits pulmonary inflammation and tissue remodeling in COPD rats, indicating its modulation of additional Gαq-associated pathological processes. Thus, our results suggest that Tas2R activation may be an ideal strategy for halting multiple pathological processes of COPD.

• Authors: Yu-Wei Zhou, Jie Sun, Ye Wang, Cai-Ping Chen, Tao Tao, Ming Ma, Xin Chen, Xue-Na Zhang, Li-Yuan Yang, Zhong-Liang Zhang, Ye-Qiong Li, Zhi-Hui Jiang, Tian-Tian Qiu, Han Wang, Yang Pan, Jian Zhang, Hua-Qun Chen, Pei Wang, Min-Sheng Zhu
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 119 Issue 26 Pg. e2121513119 (06 28 2022) ISSN: 1091-6490 [Electronic] United States
• PMID: 35737832 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bronchodilator Agents
• Receptors, G-Protein-Coupled
• Calcium

Topics

• Animals
• Asthma (genetics, metabolism, physiopathology)
• Bronchodilator Agents (pharmacology)
• Calcium (metabolism)
• Muscle, Smooth (drug effects, metabolism)
• Myocytes, Smooth Muscle (drug effects, metabolism)
• Pulmonary Disease, Chronic Obstructive (genetics, physiopathology)
• Rats
• Receptors, G-Protein-Coupled (genetics, metabolism)
• Signal Transduction
• Transcriptional Activation