Vox, PKR activator, and GBT021601 enhance HbSS RBC deformability under hypoxia through distinct mechanisms. (A) In untreated HbSS cells, increased deoxygenation drives extensive HbSS polymerization, membrane deformation, and stretching; this elevated tension robustly activates Piezo1 channels, leading to marked influx, ATP depletion, and secondary reductions in 2,3-DPG. The resultant [Ca2+]total overload triggers Band 3 phosphorylation, dissociation from the spectrin-actin-protein 4.1 network, and severe loss of deformability. (B) Vox increases Hb-O2 affinity under hypoxia, preventing residual polymer formation and membrane stress. Reduced Piezo1 activation limits influx, whereas improved membrane tension maintains residual PMCA activity. Together, these actions lower intracellular [Ca2+]total, reduce Band 3 phosphorylation, preserve cytoskeletal cohesion, and improve deformability. (C) PKR activators increase PKR activity to elevate ATP and lower 2,3-DPG during hypoxia. Higher ATP increases PMCA activity and reduced 2,3-DPG raises Hb-O2 affinity, both of which inhibit Piezo1 and [Ca2+]total accumulation. Restored [Ca2+]total homeostasis attenuates Band 3 phosphorylation and stabilizes the membrane-cytoskeleton complex. (D) GBT021601 combines R-state stabilization with robust 2,3-DPG lowering under hypoxia, suppressing HbSS polymerization and membrane tension. This dual effect limits Piezo1 and supports residual PMCA activity, thereby reducing [Ca2+]total levels, decreasing Band 3 phosphorylation, and markedly enhancing RBC deformability.
Figure 6.

Vox, PKR activator, and GBT021601 enhance HbSS RBC deformability under hypoxia through distinct mechanisms. (A) In untreated HbSS cells, increased deoxygenation drives extensive HbSS polymerization, membrane deformation, and stretching; this elevated tension robustly activates Piezo1 channels, leading to marked influx, ATP depletion, and secondary reductions in 2,3-DPG. The resultant [Ca2+]total overload triggers Band 3 phosphorylation, dissociation from the spectrin-actin-protein 4.1 network, and severe loss of deformability. (B) Vox increases Hb-O2 affinity under hypoxia, preventing residual polymer formation and membrane stress. Reduced Piezo1 activation limits influx, whereas improved membrane tension maintains residual PMCA activity. Together, these actions lower intracellular [Ca2+]total, reduce Band 3 phosphorylation, preserve cytoskeletal cohesion, and improve deformability. (C) PKR activators increase PKR activity to elevate ATP and lower 2,3-DPG during hypoxia. Higher ATP increases PMCA activity and reduced 2,3-DPG raises Hb-O2 affinity, both of which inhibit Piezo1 and [Ca2+]total accumulation. Restored [Ca2+]total homeostasis attenuates Band 3 phosphorylation and stabilizes the membrane-cytoskeleton complex. (D) GBT021601 combines R-state stabilization with robust 2,3-DPG lowering under hypoxia, suppressing HbSS polymerization and membrane tension. This dual effect limits Piezo1 and supports residual PMCA activity, thereby reducing [Ca2+]total levels, decreasing Band 3 phosphorylation, and markedly enhancing RBC deformability.

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