Action potential–independent spontaneous microdomain Ca 2+ transients–mediated continuous neurotransmission regulates hyperalgesia

IF 9.4 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-01-17 DOI:10.1073/pnas.2406741122
Zhuoyu Zhang, Jingyu Yao, Jingxiao Huo, Ruolin Wang, Xueting Duan, Yang Chen, Huadong Xu, Changhe Wang, Zuying Chai, Rong Huang
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Abstract

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 Ca 2+ (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.
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动作电位不依赖的自发微域ca2 +瞬态介导的连续神经传递调节痛觉过敏
神经递质和神经调节剂可以通过动作电位(AP)诱发的短暂或不依赖于AP的连续神经传递释放。ap诱发的初级感觉神经元神经传递升高在痛觉过敏中起着至关重要的作用。然而,不依赖ap的连续神经传递是否以及如何导致痛觉过敏在很大程度上仍然未知。在这里,我们发现初级感觉背根神经节(DRG)神经元在细胞体和轴突上表现出频繁的独立于APs的自发微域ca2 + (smCa)活性,这是由TRPA1通道的自发打开介导的,并通过环腺苷单磷酸蛋白激酶A信号通路触发连续的神经传递。更重要的是,在经历炎症性疼痛的小鼠中,smCa活性及其引发的DRG神经元持续神经传递的频率显著增加,抑制smCa活性可减轻痛觉过敏。总的来说,这项工作揭示了DRG神经元中smCa活性引发的ap不依赖的连续神经传递,这可能是痛觉过敏中伤害性致敏的独特机制,并为慢性疼痛的治疗提供了潜在的靶点。
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来源期刊
CiteScore
19.00
自引率
0.90%
发文量
3575
审稿时长
2.5 months
期刊介绍: The Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed journal of the National Academy of Sciences (NAS), serves as an authoritative source for high-impact, original research across the biological, physical, and social sciences. With a global scope, the journal welcomes submissions from researchers worldwide, making it an inclusive platform for advancing scientific knowledge.
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