Trpv1 and Trpa1 are not essential for Psickle-like activity in red cells of the SAD mouse model of sickle cell disease

• Published in: Blood cells, molecules, & diseases Vol. 92; p. 102619
• Main Authors: Vandorpe, David H., Rivera, Alicia, Shmukler, Boris E., Wohlgemuth, Jay G., Dlott, Jeffrey S., Snyder, L. Michael, Trudel, Marie, Brugnara, Carlo, Alper, Seth L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2021
• Subjects: Anemia, Sickle Cell - genetics; Anemia, Sickle Cell - metabolism; Anemia, Sickle Cell - pathology; Animals; Calcium; Cation channel; Cations - metabolism; Deoxygenation; Disease Models, Animal; Erythrocyte; Erythrocytes - metabolism; Erythrocytes - pathology; Gene Deletion; Humans; Hypoxia; Mice; Mice, Knockout; Radioisotopic flux; TRPA1 Cation Channel - genetics; TRPA1 Cation Channel - metabolism; TRPV Cation Channels - genetics; TRPV Cation Channels - metabolism; Erythrocyte; Hypoxia; Radioisotopic flux; Cation channel; Calcium; Deoxygenation
• ISSN: 1079-9796; 1096-0961
• DOI: 10.1016/j.bcmd.2021.102619

The molecular identity of Psickle, the deoxygenation-activated cation conductance of the human sickle erythrocyte, remains unknown. We observed in human sickle red cells that inhibitors of TRPA1 and TRPV1 inhibited Psickle, whereas a TRPV1 agonist activated a Psickle-like cation current. These observations prompted us to test the roles of TRPV1 and TRPA1 in Psickle in red cells of the SAD mouse model of sickle cell disease. We generated SAD mice genetically deficient in either TRPV1 or TRPA1. SAD;Trpv1−/− and SAD;Trpa1−/− mice were indistinguishable in appearance, hematological indices, and osmotic fragility from SAD mice. We found that deoxygenation-activated cation currents remained robust in SAD;Trpa1−/− and SAD;Trpv1−/− mice. In addition, 45Ca2+ influx into SAD mouse red cells during prolonged deoxygenation was not reduced in red cells from SAD;Trpa1−/− and SAD;Trpv1−/− mice. We conclude that the nonspecific cation channels TRPA1 and TRPV1 are not required for deoxygenation to stimulate Psickle-like activity in red cells of the SAD mouse model of sickle cell disease. (159) •Inhibition of human SS RBC Psickle by blockers of TRPA1 and TRPV1 prompted us to test the role of TRPA1 and TRPV1 expression in Psickle activity of RBC of the SAD mouse model of sickle cell disease.•SAD;Trpa1−/− and SAD;Trpv1−/− mice were grossly indistinguishable from SAD mice.•Cation currents in on-cell patch recordings of red cells from SAD:Trpa1−/− and SAD;Trpv1−/− mice were activated by deoxygenation in a manner similar to that of deoxygenation-activated Psickle currents in SAD mouse red cells.•45Ca2+ influx measured during tonic deoxygenation of SAD red cells was not diminished in red cells from SAD;Trpa1−/− and SAD;Trpv1−/− mice.