A functional interaction between a region of the SARS-CoV-2 spike protein and the human α7 nicotinic receptor

Abstract

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The binding of the viral spike protein (S) to angiotensin-converting enzyme 2 in host cells is crucial for infection. The S protein has been suggested to interact with nicotinic acetylcholine receptors (nAChRs), and their contribution to the COVID-19 inflammatory pathophysiology has been proposed. α7 is an interesting candidate target because it is present in neuronal and non-neuronal cells, and it has neuroprotective and anti-inflammatory actions. By whole-cell and single-channel recordings we revealed that the Y674-R685 region of the S protein shows a direct functional interaction with human α7 nAChR. The S fragment exerts a dual effect, acting as a low-efficacy agonist and a non-competitive antagonist. In agreement with molecular dynamics simulations showing stable binding of this region to the ACh binding pocket, the S fragment activates α7, but only in the presence of a potentiator, supporting its action as a very low-efficacy agonist. In addition, it allosterically inhibits α7 responses elicited by ACh, which may result in the predominant effect. This study provides unequivocal evidence supporting a functional α7-S protein interaction, which may play a role in infectivity and/or disease progression and may be explored for new therapeutic opportunities.