Sickle-induced non-selective cation leak pathway (Psickle) (Psickle)

The sickle-induced non-selective cation leak pathway, commonly referred to as Psickle, is a pathological conductance activated in red blood cells of patients with sickle cell disease (SCD) upon deoxygenation (Lew & Bookchin, 2005, PMID: 16102035). When hemoglobin S polymerizes and deforms the erythrocyte membrane, this pathway allows the influx of sodium and calcium ions and the efflux of potassium ions (Tiffert et al., 2003, PMID: 12609837). The resulting increase in intracellular calcium activates the Gardos channel (KCNN4), leading to rapid potassium and water loss, which causes cell dehydration and increases the concentration of hemoglobin S, accelerating further sickling (Brugnara, 2018, PMID: 29632015). While its exact molecular identity has been a subject of debate, recent evidence suggests the involvement of mechanosensitive channels like Piezo1 (Cahalan et al., 2015, PMID: 25833811) or N-methyl-D-aspartate (NMDA) receptors (Makhro et al., 2013, PMID: 23894650). Therapeutic strategies targeting Psickle aim to prevent the ionic imbalances that lead to the formation of dense, dehydrated sickle cells, thereby reducing vaso-occlusive crises and hemolytic anemia (Hänggi et al., 2014, PMID: 25293561).

Other names

PsickleDeoxygenation-induced cation conductanceSickle-induced cation leakP-sickleDeoxygenation-induced pathwaySickle-induced cation pathway

Inhibition of the deoxygenation-induced non-selective cation conductance to prevent calcium influx and subsequent cell dehydration.