NOTE: TMEM16 stands for Transmembrane 16 proteins. There are 10 such proteins. TMEM16A is also known as Anoctamin-1, transcoded by the ANO1 gene. Anoctamin-1 is a voltage-gated calcium-activated anion channel, which acts as a chloride channel and a bicarbonate channel. ANO1 is also responsible for most of the iodide efflux across the apical membrane of thyroid cells (Twyffels et al., 2014).
"TMEM16x proteins are typically activated by agonist-induced Ca2+ release evoked by Gq-protein-coupled receptor (GqPCR) activation; thus, TMEM16x proteins link Ca2+-signalling with cell electrical activity and/or lipid transport." (Agostinelli & Tammaro, 2022)
Agostinelli E, Tammaro P - "Polymodal Control of TMEM16x Channels and Scramblases" Int J Mol Sci 23(3):1580 (2022)
8. A Role for TMEM16F in the Pathology of SARS-CoV-2
TMEM16F may also play a role in the pathogenesis of SARS-CoV-2. A characteristic feature of SARS-CoV-2 infection is the formation of pneumocyte syncytia, which involves viral spike protein cleavage by host cell proteases [285,286]. Cells expressing SARS-CoV-2 spike proteins have enhanced Ca2+ oscillations and increased TMEM16F activity, leading to PS externalisation, which promotes syncytia formation . SARS-CoV-2 spike proteins may (1) promote Ca2+ release and, thus, activation of TMEM16F scrambling in infected cells (cis modality), and/or (2) stimulate activation of proteases on neighbouring cells, triggering cell fusion (trans modality) . The involvement of TMEM16F in SARS-CoV-2 spike-induced syncytia is supported by the role of PS exposure in a range of other physiological cell fusion events [287,288,289,290,291]. Niclosamide—a therapeutic anthelmintic drug utilised for the treatment of tapeworm infections—reduces syncytial formation by inhibiting TMEM16F activity, and could be repurposed for the treatment of SARS-CoV-2 [29,292].
The TMEM16x family of Ca2+-activated channels and scramblases provides a link between intracellular Ca2+ handling and ion/lipid transport. It is becoming apparent that these proteins respond to a range of additional cellular factors, highlighting their capacity to serve as sensors of cellular homeostasis. Uncovering these intricate mechanisms of regulation will enable a more complete understanding of the TMEM16x physiological roles and aid in the exploitation of these potential pharmacological targets for the treatment of a range of human diseases, including stroke, hypertension, vascular dementia, cystic fibrosis, and cancer.
Niclosamide & COVID Treatment
Braga L, Ali H, Secco I, Chiavacci E, Neves G, Goldhill D, Penn R, Jimenez-Guardeño JM, Ortega-Prieto AM, Bussani R, Cannatà A, Rizzari G, Collesi C, Schneider E, Arosio D, Shah AM, Barclay WS, Malim MH, Burrone J, Giacca M - "Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia" Nature 594(7861):88-93 (2021)
"One of the most effective molecules was the antihelminthic drug niclosamide, which markedly blunted calcium oscillations and membrane conductance in spike-expressing cells by suppressing the activity of TMEM16F (also known as anoctamin 6), a calcium-activated ion channel and scramblase that is responsible for exposure of phosphatidylserine on the cell surface. These findings suggest a potential mechanism for COVID-19 disease pathogenesis and support the repurposing of niclosamide for therapy."
Weiss A, Touret F, Baronti C, Gilles M, Hoen B, Nougairède A, de Lamballerie X, Sommer MOA - "Niclosamide shows strong antiviral activity in a human airway model of SARS-CoV-2 infection and a conserved potency against the Alpha (B.1.1.7), Beta (B.1.351) and Delta variant (B.1.617.2)" PLoS One. 2021 Dec 2;16(12):e0260958. doi: 10.1371/journal.pone.0260958. PMID: 34855904; PMCID: PMC8639074
https://journals.plos.org/plosone/artic ... ne.0260958
Singh S, Weiss A, Goodman J, Fisk M, Kulkarni S, Lu I, Gray J, Smith R, Sommer M, Cheriyan J - "Niclosamide-A promising treatment for COVID-19" Br J Pharmacol. 2022 Mar 29. doi: 10.1111/bph.15843. Epub ahead of print. PMID: 35348204
Wang G, Gaikwad H, McCarthy MK, Gonzalez-Juarrero M, Li Y, Armstrong M, Reisdorph N, Morrison TE, Simberg D - "Lipid nanoparticle formulation of niclosamide (nano NCM) effectively inhibits SARS-CoV-2 replication in vitro" Precis Nanomed 4(1):724-737 (2021)
Thyroid and TMEM16
Twyffels L, Strickaert A, Virreira M, Massart C, Van Sande J, Wauquier C, Beauwens R, Dumont JE, Galietta LJ, Boom A, Kruys V - "Anoctamin-1/TMEM16A is the major apical iodide channel of the thyrocyte" Am J Physiol Cell Physiol 307(12):C1102-12 (2014)
https://journals.physiology.org/doi/ful ... ossref.org
Other papers of interest:
Pinto MC, Silva IAL, Figueira MF, Amaral MD, Lopes-Pacheco M - "Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis" J Exp Pharmacol 13:693-723 (2021)
https://www.dovepress.com/pharmacologic ... rticle-JEP
Ta CM, Acheson KE, Rorsman NJG, Jongkind RC, Tammaro P - "Contrasting effects of phosphatidylinositol 4,5-bisphosphate on cloned TMEM16A and TMEM16B channels" Br J Pharmacol 174(18):2984-2999 (2017)
https://bpspubs.onlinelibrary.wiley.com ... /bph.13913
More on Niclosamide
Chen W, Mook RA Jr, Premont RT, Wang J - "Niclosamide: Beyond an antihelminthic drug" Cell Signal 41:89-96 (2018) doi: 10.1016/j.cellsig.2017.04.001. Epub 2017 Apr 4. PMID: 28389414; PMCID: PMC5628105.
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