Abstract
The pathophysiological mechanisms underlying the constellation of symptoms that characterize COVID-19 are only incompletely understood. In an effort to fill these gaps, a “nicotinic hypothesis,” which posits that nicotinic acetylcholine receptors (AChRs) act as additional severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptors, has recently been put forth. A key feature of the proposal (with potential clinical ramifications) is the suggested competition between the virus’ spike protein and small-molecule cholinergic ligands for the receptor’s orthosteric binding sites. This notion is reminiscent of the well-established role of the muscle AChR during rabies virus infection. To address this hypothesis directly, we performed equilibrium-type ligand-binding competition assays using the homomeric human α7-AChR (expressed on intact cells) as the receptor, and radio-labeled α-bungarotoxin (α-BgTx) as the orthosteric-site competing ligand. We tested different SARS-CoV-2 spike protein peptides, the S1 domain, and the entire S1-S2 ectodomain, and found that none of them appreciably outcompete [ 125 I]-α-BgTx in a specific manner. Furthermore, patch-clamp recordings showed no clear effect of the S1 domain on α7-AChR-mediated currents. We conclude that the binding of the SARS-CoV-2 spike protein to the human α7-AChR’s orthosteric sites-and thus, its competition with ACh, choline, or nicotine-is unlikely to be a relevant aspect of this complex disease.
Keywords: SARS-CoV-2; acetylcholine receptors; binding competition assays; nicotinic receptors; spike protein.
【저자키워드】 SARS-CoV-2, spike protein., acetylcholine receptors, nicotinic receptors, binding competition assays, 【초록키워드】 COVID-19, coronavirus, Infection, Symptom, virus, Spike protein, cells, SARS-CoV-2 spike protein, peptides, receptors, receptor, disease, binding, Rabies virus, Ligand, Hypothesis, acute respiratory syndrome, complex, effort, pathophysiological mechanism, ectodomain, S1 domain, tested, performed, unlikely, expressed, suggested, competing, the SARS-CoV-2, 【제목키워드】 COVID-19, Hypothesis,