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Regulation of epithelial sodium channel activity by SARS-CoV-1 and SARS-CoV-2 proteins

Grant, Stephen N. and Lester, Henry A. (2021) Regulation of epithelial sodium channel activity by SARS-CoV-1 and SARS-CoV-2 proteins. Biophysical Journal, 120 (14). pp. 2805-2813. ISSN 0006-3495. PMCID PMC8238646. doi:10.1016/j.bpj.2021.06.005.

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Severe acute respiratory syndrome (SARS) coronavirus (CoV) 2 (SARS-CoV-2), which causes the coronavirus disease 2019, encodes several proteins whose roles are poorly understood. We tested their ability either to directly form plasma membrane ion channels or to change functions of two mammalian plasma membrane ion channels, the epithelial sodium channel (ENaC) and the α3β4 nicotinic acetylcholine receptor. In mRNA-injected Xenopus oocytes, none of nine SARS-CoV-2 proteins or two SARS-CoV-1 proteins produced conductances, nor did co-injection of several combinations. Immunoblots for ORF8, spike (S), and envelope (E) proteins revealed that the proteins are expressed at appropriate molecular weights. In experiments on coexpression with ENaC, three tested SARS proteins (SARS-CoV-1 E, SARS-CoV-2 E, and SARS-CoV-2 S) markedly decrease ENaC currents. SARS-CoV-1 S protein decreases ENaC currents modestly. Coexpressing the E proteins but not the S proteins with α3β4 nicotinic acetylcholine receptors significantly reduces acetylcholine-induced currents. ENaC inhibition does not occur if the SARS-CoV protein mRNAs are injected 24 h after the ENaC mRNAs, suggesting that SARS-CoV proteins affect early step(s) in functional expression of channel proteins. Consistent with the hypothesis that the SARS-CoV-2 S protein-induced ENaC inhibition involves competition for available protease, mutating the furin cleavage site in SARS-CoV-2 S protein partially relieves inhibition of ENaC currents. Extending previous suggestions that SARS proteins affect ENaC currents via protein kinase C (PKC) activation, PKC activation via phorbol 12-myristate 13-acetate decreases ENaC and α3β4 activity. Phorbol 12-myristate 13-acetate application reduced membrane capacitance ∼5%, presumably via increased endocytosis, but this decrease is much smaller than the SARS proteins’ effects on conductances. Also, incubating oocytes in Gö-6976, a PKCα and PKCβ inhibitor, did not alter E or S protein-induced channel inhibition. We conclude that SARS-CoV-1 and SARS-CoV-2 proteins alter the function of human plasma membrane channels, via incompletely understood mechanisms. These interactions may play a role in the coronavirus 2019 pathophysiology.

Item Type:Article
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URLURL TypeDescription CentralArticle
Grant, Stephen N.0000-0003-0923-8886
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2021 Biophysical Society. Received 15 December 2020, Accepted 3 June 2021, Available online 29 June 2021. We thank Drs. Christopher Barnes, Bruce N. Cohen, Douglas Eaton, Carolyn Machamer, Gerhard Thiel, Anthony West, Nael McCarty, Dennis A. Dougherty and Nathan Dascal for useful insights, and Jonathan Wang for harvesting oocytes. This work was supported by the National Institute of Drug Abuse (DA046122 and DA049140), the National Institute of General Medical Sciences (GM-123582), and the California Tobacco-Related Disease Program (29IR0445 to D.A. Dougherty). Author contributions: S.N.G. designed and performed the experiments, analyzed the data, and prepared the manuscript. H.A.L. designed the experiments, analyzed the data, prepared the manuscript, and supervised the project.
Funding AgencyGrant Number
National Institute on Drug AbuseUNSPECIFIED
California Tobacco-Related Disease Research Program29IR0445
Issue or Number:14
PubMed Central ID:PMC8238646
Record Number:CaltechAUTHORS:20210714-140716932
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Official Citation:Stephen N. Grant, Henry A. Lester, Regulation of epithelial sodium channel activity by SARS-CoV-1 and SARS-CoV-2 proteins, Biophysical Journal, Volume 120, Issue 14, 2021, Pages 2805-2813, ISSN 0006-3495,
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:109801
Deposited By: Tony Diaz
Deposited On:14 Jul 2021 18:38
Last Modified:28 Jul 2021 19:25

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