Alpha7 Nicotinic Receptor: Structures and Coupling with Intracellular Proteins

α7烟碱型乙酰胆碱受体(α7nAChR)在感染和感染中发挥着独特的作用。 新冠肺炎的进展，已导致超过325,000人死亡。α7nAChR将吸烟与 新冠肺炎的主要临床表现，包括呼吸道感染、嗅觉障碍、全身凝血障碍和 细胞因子风暴。SARS-CoV-2的几个序列与α-银环蛇毒素和α-CoV2同源。 眼镜蛇毒是α7nAChR的强效拮抗剂。这些发现支持SARS-CoV-2相互作用的假设 直接与α7nAChR结合，抑制其功能，从而失调介导的炎症反应 作者：α7nAChR。迫切需要实验证据来正确确定α7nAChR在 新冠肺炎和了解尼古丁在COVID发生和发展中的有害或保护作用- 19.得到NIDA的许可(罗杰·利特尔博士，神经科学和行为司副主任)， 我们寻求行政补充支持，以解决有关尼古丁参与的几个关键问题 新冠肺炎中的α7nAChR。具体地说，我们建议阐明：(1)SARS-CoV-2蛋白在哪里以及如何 与α7nAChR的相互作用以及尼古丁如何改变这种相互作用；以及(2)SARS-CoV-2蛋白如何影响 α7nAChR下游导致前-乙酰胆碱受体上调和反式激活的细胞内信号通路 炎症细胞因子，以及尼古丁如何调节这一过程的结果。考虑到广泛存在的 α7nAChR在不同器官中的表达及α7nAChR在胆碱能拮抗剂中的调节作用 炎症途径，我们的研究成果可能会导致新的治疗策略来对抗 新冠肺炎。

The alpha7 nicotinic acetylcholine receptor (α7nAChR) has emerged as a unique player in the infection and progression of COVID-19, which has caused more than 325,000 deaths. α7nAChR links tobacco smoking to major clinical manifestations in COVID-19, including respiratory infection, anosmia, systemic coagulopathy, and cytokine storm. Several sequences of SARS-CoV-2 are found to be homologous to α-bungarotoxin and α- cobratoxin, potent antagonists of α7nAChR. These findings support the hypothesis that SARS-CoV-2 interacts directly with α7nAChR, inhibits its function, and consequently dysregulates the inflammatory responses mediated by α7nAChR. The experimental evidence is urgently needed to correctly establish the role of α7nAChR in COVID-19 and to understand nicotine’s detrimental or protective effects on the onset and progression of COVID- 19. With permission from the NIDA (Dr. Roger Little, Deputy Director, Division of Neuroscience and Behavior), we seek Administrative Supplement support to address several key questions about the involvement of nicotine and α7nAChR in COVID-19. Specifically, we propose to elucidate: (1) where and how SARS-CoV-2 proteins interact with α7nAChR and how nicotine alters such interactions; and (2) how SARS-CoV-2 proteins affect intracellular signaling pathways downstream of α7nAChR that lead to upregulation and transactivation of pro- inflammatory cytokines, and how nicotine modulates the outcome of this process. Considering the widespread expression of α7nAChR in various organs and the significant regulatory role of α7nAChR in the cholinergic anti- inflammatory pathway, our research outcomes can potentially lead to new treatment strategies to combat COVID-19.