The TRPV2 channel mediates Ca2+ influx and the Δ9-THC-dependent decrease in osmotic fragility in red blood cells

Abstract

Water and ionic homeostasis of red blood cells (RBC) is regulated by various active and passive transport mechanisms in the RBC membrane, including channels like aquaporins, 1 the mechanically activated non-selective cation channel Piezo12 and the Ca2+-activated potassium channel KCa3.1.3 The human genome contains 27 genes that code for transient receptor potential (TRP) channels. The only TRP channel protein that has been detected in circulating mouse RBC is TRPC6,4 which might be associated with basal Ca2+ leakage and stress-stimulated Ca2+ entry.4 TRPC2 and TRPC3 are expressed by murine erythroid precursors and splenic erythroblasts, and in these cells, erythropoietin stimulates an increase in intracellular calcium concentration via TRPC2 and TRPC3.5 In this study we identified the TRP vanilloid (TRPV) 2 channel protein in mouse and human RBC by specific antibodies and mass spectrometry. TRPV2-dependent currents and Ca2+ entry were activated by the TRPV2 agonists cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC)6 resulting in a leftshift of the hypotonicity-dependent hemolysis curve. This effect was reversed in the presence of the KCa3.1 inhibitor TRAM-34, whereas the knockout of Trpv2 right-shifted the hemolysis curve to higher tonicities.