The SARS-CoV-2 Virus and the Cholinergic System: Spike Protein Interaction with Human Nicotinic Acetylcholine Receptors and the Nicotinic Agonist Varenicline

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the worldwide coronavirus disease 2019 (COVID-19) pandemic. Although the pathophysiology of SARS-CoV-2 infection is still being elucidated, the nicotinic cholinergic system may play a role. To evaluate the interaction of the SARS-CoV-2 virus with human nicotinic acetylcholine receptors (nAChRs), we assessed the in vitro interaction of the spike protein of the SARS-CoV-2 virus with various subunits of nAChRs. Electrophysiology recordings were conducted at alpha 4 beta 2, alpha 3 beta 4, alpha 3 alpha 5 beta 4, alpha 4 alpha 6 beta 2, and alpha 7 neuronal nAChRs expressed in Xenopus oocytes. In cells expressing the alpha 4 beta 2 or alpha 4 alpha 6 beta 2 nAChRs, exposure to the 1 mu g/mL Spike-RBD protein caused a marked reduction of the current amplitude; effects at the alpha 3 alpha 5 beta 4 receptor were equivocal and effects at the alpha 3 beta 4 and alpha 7 receptors were absent. Overall, the spike protein of the SARS-CoV-2 virus can interact with select nAChRs, namely the alpha 4 beta 2 and/or alpha 4 alpha 6 beta 2 subtypes, likely at an allosteric binding site. The nAChR agonist varenicline has the potential to interact with Spike-RBD and form a complex that may interfere with spike function, although this effect appears to have been lost with the omicron mutation. These results help understand nAChR's involvement with acute and long-term sequelae associated with COVID-19, especially within the central nervous system.

Automated summary

The spike protein of SARS-CoV-2 can interact with select nicotinic acetylcholine receptors, specifically the alpha 4 beta 2 and/or alpha 4 alpha 6 beta 2 subtypes. This finding helps us understand the involvement of nicotinic acetylcholine receptors in acute and long-term sequelae associated with COVID-19, especially within the central nervous system.