机构：[1]Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou, 310053, China[2]Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China[3]Department of Immune-oncology, the Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, China河北医科大学第四医院[4]Department of Pharmacology, Hebei Medical University, Shijiazhuang, 050017, China[5]Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, 27710, United States of America
Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor that has been widely known as a pain mediator involved in various pain states. Evidence indicates that ET-1 sensitizes transient receptor potential cation channel, subfamily A, member 1 (TRPA1) in vivo. But the molecular mechanisms still remain unknown. We aim to explore whether ET-1 sensitizes TRPA1 in primary sensory neurons and the molecular mechanisms. Ca2+ imaging, immunostaining, electrophysiology, animal behavioral assay combined with pharmacological experiments were performed. ET-1 sensitized TRPA1-mediated Ca2+ responses in human embryonic kidney (HEK)293 cells as well as in cultured native mouse dorsal root ganglion (DRG) neurons. ET-1 also sensitized TRPA1 channel currents. ET-1 sensitized TRPA1 activated by endogenous agonist H2O2. ETA receptor (ETAR) colocalized with TRPA1 in DRG neurons. ET-1-induced TRPA1 sensitization in vivo was mediated via ETAR and protein kinase A (PKA) pathway in HEK293 cells and DRG neurons. Pharmacological blocking of ETAR, PKA, and TRPA1 significantly attenuated ET-1-induced mechanical hyperalgesia in mice. Our results suggest that TRPA1 acts as a molecular target for ET-1, and sensitization of TRPA1 through ETAR-PKA pathway contributes to ET-1-induced mechanical hyperalgesia. Pharmacological targeting of TRPA1 and ETAR-PKA pathway may provide effective strategies to alleviate pain conditions associated with ET-1.
基金：
Zhejiang Provincial Natural Science Funds for Distinguished Young Scholars [LR17H270001]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81873365, 81603676, 81770407, 81574056]; Qianjiang Talent Program [QJD1702020]; Zhejiang Chinese Medical University [2018ZY37, 2018ZY19]; Scientific Research Foundation for the Returned Overseas Chinese Scholars of Hebei ProvinceScientific Research Foundation for the Returned Overseas Chinese Scholars; National Institute of Arthritis and Musculoskeletal and Skin DiseaseUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) [R21AR070554]; Administration of Traditional Chinese Medicine of Hebei Province [2018139]; NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) [R21AR070554, R21AR070554] Funding Source: NIH RePORTER
第一作者机构：[1]Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou, 310053, China
共同第一作者：
通讯作者：
通讯机构：[1]Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou, 310053, China[5]Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, 27710, United States of America[*1]Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310053, China.[*2]Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, 27710, USA.
推荐引用方式(GB/T 7714)：
Zheng Xiaoli,Tai Yan,He Dongwei,et al.ETAR and protein kinase A pathway mediate ET-1 sensitization of TRPA1 channel: A molecular mechanism of ET-1-induced mechanical hyperalgesia[J].MOLECULAR PAIN.2019,15:doi:10.1177/1744806919842473.
APA：
Zheng, Xiaoli,Tai, Yan,He, Dongwei,Liu, Boyu,Wang, Chuan...&Liu, Boyi.(2019).ETAR and protein kinase A pathway mediate ET-1 sensitization of TRPA1 channel: A molecular mechanism of ET-1-induced mechanical hyperalgesia.MOLECULAR PAIN,15,
MLA：
Zheng, Xiaoli,et al."ETAR and protein kinase A pathway mediate ET-1 sensitization of TRPA1 channel: A molecular mechanism of ET-1-induced mechanical hyperalgesia".MOLECULAR PAIN 15.(2019)
