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钙激活离子通道驱动内侧缰核神经元的非典型抑制。

Calcium-activated ion channels drive atypical inhibition in medial habenula neurons.

作者信息

Kawai Takafumi, Dong Ping, Bakhurin Konstantin, Yin Henry H, Yang Huanghe

机构信息

Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.

Integrative Physiology, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan.

出版信息

Sci Adv. 2025 Mar 21;11(12):eadq2629. doi: 10.1126/sciadv.adq2629. Epub 2025 Mar 19.

DOI:10.1126/sciadv.adq2629
PMID:40106550
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11922023/
Abstract

Nicotine is an addictive substance that poses substantial health and societal challenges. Despite the known links between the medial habenula (MHb) and nicotine avoidance, the ionic mechanisms underlying MHb neuronal responses to nicotine remain unclear. Here, we report that MHb neurons use a long-lasting refractory period (LLRP) as an unconventional inhibitory mechanism to curb hyperexcitability. This process is initiated by nicotine-induced calcium influx through nicotinic acetylcholine receptors, which activates a calcium-activated chloride channel (CaCC). Owing to high intracellular chloride levels in MHb neurons, chloride efflux through CaCC, coupled with high-threshold voltage-gated calcium channels, sustains MHb depolarization near the chloride equilibrium potential of -30 millivolts, thereby enabling LLRP. Concurrently, calcium-activated BK potassium channels counteract this depolarization, promoting LLRP termination. Our findings reveal an atypical inhibitory mechanism, orchestrated by synergistic actions between calcium-permeable and calcium-activated channels. This discovery advances our understanding of neuronal excitability control and nicotine addiction.

摘要

尼古丁是一种成瘾性物质，带来了重大的健康和社会挑战。尽管内侧缰核（MHb）与避免尼古丁之间的已知联系，但MHb神经元对尼古丁反应的离子机制仍不清楚。在这里，我们报告MHb神经元使用持久不应期（LLRP）作为一种非常规的抑制机制来抑制过度兴奋。这个过程由尼古丁通过烟碱型乙酰胆碱受体诱导的钙内流启动，该受体激活钙激活氯通道（CaCC）。由于MHb神经元内氯离子水平较高，通过CaCC的氯离子外流，与高阈值电压门控钙通道一起，在氯离子平衡电位-30毫伏附近维持MHb去极化，从而实现LLRP。同时，钙激活的BK钾通道抵消这种去极化，促进LLRP终止。我们的发现揭示了一种非典型的抑制机制，由钙通透通道和钙激活通道之间的协同作用精心安排。这一发现推进了我们对神经元兴奋性控制和尼古丁成瘾的理解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06c9/11922023/b2cb40a0131a/sciadv.adq2629-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06c9/11922023/7a9ceadeafba/sciadv.adq2629-f1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06c9/11922023/8263d0ef689f/sciadv.adq2629-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06c9/11922023/a4fb000706c8/sciadv.adq2629-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06c9/11922023/9482ee4b20ce/sciadv.adq2629-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06c9/11922023/e7f059649496/sciadv.adq2629-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06c9/11922023/b2cb40a0131a/sciadv.adq2629-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06c9/11922023/7a9ceadeafba/sciadv.adq2629-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06c9/11922023/a2fe2b60dcba/sciadv.adq2629-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06c9/11922023/c4eb0c819707/sciadv.adq2629-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06c9/11922023/77224aec7cf3/sciadv.adq2629-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06c9/11922023/8263d0ef689f/sciadv.adq2629-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06c9/11922023/a4fb000706c8/sciadv.adq2629-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06c9/11922023/9482ee4b20ce/sciadv.adq2629-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06c9/11922023/e7f059649496/sciadv.adq2629-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06c9/11922023/b2cb40a0131a/sciadv.adq2629-f9.jpg

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Conditional deletion of TMEM16A in cholinergic neurons of the medial habenula induces anhedonic-like behavior in mice.条件性敲除缰核胆碱能神经元 TMEM16A 可诱导小鼠出现快感缺失样行为。
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