{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:30:54Z","timestamp":1790663454961,"version":"4.1.0"},"reference-count":66,"publisher":"National Academy of Sciences","issue":"44","license":[{"start":{"date-parts":[[2022,10,24]],"date-time":"2022-10-24T00:00:00Z","timestamp":1666569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH\/NINDS","award":["R01-NS042169"],"award-info":[{"award-number":["R01-NS042169"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:p>\n                    The pathophysiological mechanisms underlying the constellation of symptoms that characterize COVID-19 are only incompletely understood. In an effort to fill these gaps, a \u201cnicotinic hypothesis,\u201d 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\u2019 spike protein and small-molecule cholinergic ligands for the receptor\u2019s 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 \u03b17-AChR (expressed on intact cells) as the receptor, and radio-labeled \u03b1-bungarotoxin (\u03b1-BgTx) as the orthosteric-site competing ligand. We tested different SARS-CoV-2 spike protein peptides, the S1 domain, and the entire S1\u2013S2 ectodomain, and found that none of them appreciably outcompete [\n                    <jats:sup>125<\/jats:sup>\n                    I]-\u03b1-BgTx in a specific manner. Furthermore, patch-clamp recordings showed no clear effect of the S1 domain on \u03b17-AChR\u2013mediated currents. We conclude that the binding of the SARS-CoV-2 spike protein to the human \u03b17-AChR\u2019s orthosteric sites\u2014and thus, its competition with ACh, choline, or nicotine\u2014is unlikely to be a relevant aspect of this complex disease.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2204242119","type":"journal-article","created":{"date-parts":[[2022,10,24]],"date-time":"2022-10-24T15:13:40Z","timestamp":1666624420000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":12,"title":["An experimental test of the nicotinic hypothesis of COVID-19"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5264-3719","authenticated-orcid":false,"given":"Nicole E.","family":"Godellas","sequence":"first","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Illinois at Urbana\u2013Champaign, Urbana, IL 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4155-585X","authenticated-orcid":false,"given":"Gisela D.","family":"Cymes","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Illinois at Urbana\u2013Champaign, Urbana, IL 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8093-8362","authenticated-orcid":false,"given":"Claudio","family":"Grosman","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Illinois at Urbana\u2013Champaign, Urbana, IL 61801"},{"name":"Center for Biophysics and Quantitative Biology, University of Illinois at Urbana\u2013Champaign, Urbana, IL 61801"},{"name":"Neuroscience Program, University of Illinois at Urbana\u2013Champaign, Urbana, IL 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,10,24]]},"reference":[{"key":"e_1_3_4_1_2","unstructured":"WHO WHO Coronavirus (COVID-19) Dashboard. 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