Vox, PKR activator, and GBT021601 improve HbSS RBC deformability via distinct pathways under normoxia. (A) In untreated HbSS cells, residual deoxy-HbS polymers are present, even at relatively high levels of oxygenation, and they are exacerbated by elevated 2,3-DPG, which imposes membrane tension that activates Piezo1 and elicits influx. Concurrent ATP depletion impairs PMCA, leading to [Ca2+]total overload, calpain activation, and Band 3 phosphorylation. Phosphorylated Band 3 dissociates from the spectrin-actin-protein 4.1 network, disrupting membrane cytoskeleton cohesion and thereby reducing deformability. (B) Vox covalently stabilizes HbSS in its R-state, reducing deoxy-HbS polymer formation without altering ATP or 2,3-DPG. Lower membrane tension limits Piezo1 opening and influx, normalizing [Ca2+]total. Reduced [Ca2+]total results in Band 3 dephosphorylation, maintains PMCA microdomains, and preserves cytoskeletal integrity, thereby improving deformability. (C) PKR activators enhance PKR activity to lower 2,3-DPG. Reduced 2,3-DPG increases Hb-O2 affinity, suppresses polymerization, and decreases membrane stress–induced Piezo1 activation. By preserving residual PMCA function and restoring Ca2+ homeostasis, PKR activators reduce Band 3 tyrosine phosphorylation and stabilize the spectrin-actin-protein 4.1 cytoskeletal complex, markedly improving RBC membrane integrity and deformability. (D) GBT021601 combines R-state stabilization with robust 2,3-DPG lowering. The dual effect suppresses HbS polymerization, reduces membrane tension, inhibits Piezo1, and maintains residual PMCA activity. The resulting [Ca2+]total reduction limits Band 3 phosphorylation, stabilizes the membrane-cytoskeleton network, and markedly enhances RBC deformability.
Figure 5.

Vox, PKR activator, and GBT021601 improve HbSS RBC deformability via distinct pathways under normoxia. (A) In untreated HbSS cells, residual deoxy-HbS polymers are present, even at relatively high levels of oxygenation, and they are exacerbated by elevated 2,3-DPG, which imposes membrane tension that activates Piezo1 and elicits influx. Concurrent ATP depletion impairs PMCA, leading to [Ca2+]total overload, calpain activation, and Band 3 phosphorylation. Phosphorylated Band 3 dissociates from the spectrin-actin-protein 4.1 network, disrupting membrane cytoskeleton cohesion and thereby reducing deformability. (B) Vox covalently stabilizes HbSS in its R-state, reducing deoxy-HbS polymer formation without altering ATP or 2,3-DPG. Lower membrane tension limits Piezo1 opening and influx, normalizing [Ca2+]total. Reduced [Ca2+]total results in Band 3 dephosphorylation, maintains PMCA microdomains, and preserves cytoskeletal integrity, thereby improving deformability. (C) PKR activators enhance PKR activity to lower 2,3-DPG. Reduced 2,3-DPG increases Hb-O2 affinity, suppresses polymerization, and decreases membrane stress–induced Piezo1 activation. By preserving residual PMCA function and restoring Ca2+ homeostasis, PKR activators reduce Band 3 tyrosine phosphorylation and stabilize the spectrin-actin-protein 4.1 cytoskeletal complex, markedly improving RBC membrane integrity and deformability. (D) GBT021601 combines R-state stabilization with robust 2,3-DPG lowering. The dual effect suppresses HbS polymerization, reduces membrane tension, inhibits Piezo1, and maintains residual PMCA activity. The resulting [Ca2+]total reduction limits Band 3 phosphorylation, stabilizes the membrane-cytoskeleton network, and markedly enhances RBC deformability.

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