Alpha7 Nicotinic Receptor: Structures and Coupling with Intracellular Proteins

The alpha7 nicotinic acetylcholine receptor (α7nAChR) has emerged as a unique player in the infection andprogression of COVID-19, which has caused more than 325,000 deaths. α7nAChR links tobacco smoking tomajor clinical manifestations in COVID-19, including respiratory infection, anosmia, systemic coagulopathy, andcytokine 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 interactsdirectly with α7nAChR, inhibits its function, and consequently dysregulates the inflammatory responses mediatedby α7nAChR. The experimental evidence is urgently needed to correctly establish the role of α7nAChR inCOVID-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 nicotineand α7nAChR in COVID-19. Specifically, we propose to elucidate: (1) where and how SARS-CoV-2 proteinsinteract with α7nAChR and how nicotine alters such interactions; and (2) how SARS-CoV-2 proteins affectintracellular 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 widespreadexpression 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 combatCOVID-19.