A Functional Interaction Between Y674-R685 Region of the SARS-CoV-2 Spike Protein and the Human α7 Nicotinic Receptor

The α7 nicotinic acetylcholine receptor (nAChR) is present in neuronal and non-neuronal cells and has anti-inflammatory actions. Molecular dynamics simulations suggested that α7 nAChR interacts with a region of the SARS-CoV-2 spike protein (S), and a potential contribution of nAChRs to COVID-19 pathophysiology has been proposed. We applied whole-cell and single-channel recordings to determine whether the Y674-R685 region of the S protein can directly affect α7 nAChR function. The S fragment exerts a dual effect, acting as a low-efficacy agonist and a non-competitive inhibitor. It activates α7 nAChRs, in line with our previous molecular dynamics simulations showing favorable binding of this accessible region of the S protein to the nAChR agonist binding site. However, activation requires the presence of positive allosteric modulators that enhance open probability, indicating very low efficacy. The main effect of the S fragment on α7 nAChR is a negative modulation, which is evidenced by a profound decrease in the durations of channel openings and activation episodes and in the amplitude of macroscopic responses elicited by ACh. Our study identifies a novel functional interaction between α7 nAChR and a region of the S protein, thus providing molecular foundations for exploring the involvement of nAChRs in COVID-19 pathophysiology.