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. 2021 Apr 15;12:624704. doi: 10.3389/fphar.2021.624704

FIGURE 1.

FIGURE 1

Summary of the antiviral properties of cardiac glycosides and Na+/K+-ATPase as a signal transducer. (A) Binding of SARS-CoV spike protein to the ACE2 receptor leads to membrane fusion or endocytosis, a process inhibited by ouabain and bufalin (1). Once in the cytoplasm, the viral genome is released (2) and translated into replicase proteins. The polyproteins are cleaved by a virus protease into individual replicase complex nonstructural proteins (nsps) (3), forming the replication-transcription complexes where replication begins (4). (B) Na+/K+-ATPase acts in ion transport, edema clearance, and as a signal transducer. Cardiac glycoside binding to the preassembled Na+/K+-ATPase (pump) signalosome in caveolae transduces signals via multiple pathways. Activated NKA rapidly activates Src tyrosine kinase, which activates the EGFR. Activated EGFR recruits protein adaptors that activate the Ras-GTP complex, leading to MEK pathway activation. MAPK activation triggers the opening of mitochondrial ATP-sensitive potassium channels (mitoKATP), resulting in ROS production and NFκB activation. The MEK pathway also activates NFκB through ERK ½ activation. In parallel, Src modulates the activation of the PI3K/PDK1 pathway, which is associated with viral activity and replication suppression. Activated PI3K phosphorylates Akt, which phosphorylates a variety of downstream pathways related to growth, survival, and proliferation. NKA activates phospholipase C (PLC) and inositol-1,4,5-triphosphate (IP3); the latter binds to the IP3 receptor of the endoplasmic reticulum, releasing calcium ions into the cytoplasm. Calcium oscillation activates PKC and NFκB. ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane protease serine 2; Src, non-receptor tyrosine kinases; EGFR, epithelial growth factor receptor; PKC, protein kinase C; PI3K, phosphoinositide 3′ kinase; PLC, phospholipase C; MAPK, mitogen-activated protein kinase; MEK, MAPK–ERK activating kinase; ROS, reactive oxygen species; mitoKATP, mitochondrial ATP-sensitive potassium channel.