Action potential-independent spontaneous microdomain Ca2+transients-mediated continuous neurotransmission regulates hyperalgesia

• 成果类型: Article
• 署名作者: Zhang, Zhuoyu; Yao, Jingyu; Huo, Jingxiao; Wang, Ruolin; Duan, Xueting; Chen, Yang; Xu, Huadong; Wang, Changhe; Chai, Zuying; Huang, Rong
• 署名单位: Xi'an Jiaotong University; Tongji University; Southwest Medical University; Johns Hopkins University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15319
• DOI: 10.1073/pnas.2406741122
• 发表日期: 2025-01-21
• 关键词: protein-kinase-a; anterior cingulate cortex; single synaptic vesicles; trpa1 contributes; chronic pain; release; exocytosis; neurons; nerve; phosphorylation

摘要

Neurotransmitters and neuromodulators can be released via either action potential (AP)-evoked transient or AP- independent continuous neurotransmission. The elevated AP- evoked neurotransmission in the primary sensory neurons plays crucial roles in hyperalgesia. However, whether and how the AP- independent continuous neurotransmission contributes to hyperalgesia remains largely unknown. Here, we show that primary sensory dorsal root ganglion (DRG) neurons exhibit frequent spontaneous microdomain Ca2+(smCa) activities independent of APs across the cell bodies and axons, which are mediated by the spontaneous opening of TRPA1 channels and trigger continuous neurotransmission via the cyclic adenosine monophosphate- protein kinase A signaling pathway. More importantly, the frequency of smCa activity and its triggered continuous neurotransmission in DRG neurons increased dramatically in mice experiencing inflammatory pain, inhibition of which alleviates hyperalgesia. Collectively, this work revealed the AP- independent continuous neurotransmission triggered by smCa activities in DRG neurons, which may serve as a unique mechanism underlying the nociceptive sensitization in hyperalgesia and offer a potential target for the treatment of chronic pain.