Erythrocyte ion content and dehydration modulate maximal Gardos channel activity in KCNN4 V282M/+ Hereditary Xerocytosis (HX) red cells.

Erythrocyte ion content and dehydration modulate maximal Gardos channel activity in KCNN4 V282M/+ Hereditary Xerocytosis (HX) red cells.
Am J Physiol Cell Physiol. 2019 May 15;:
Authors: Rivera A, Vandorpe DH, Shmukler BE, Andolfo I, Iolascon A, Archer NM, Shabani E, Auerbach M, Hamerschlak N, Morton J, Wohlgemuth JG, Brugnara C, Snyder LM, Alper SL
Abstract
Hereditary Xerocytosis (HX) is caused by missense mutations in either themechanosensitive cation channel, PIEZO1 or the Ca2+-activated K+ channel, KCNN4. All HX-associated KCNN4 mutants studied to date revealed increased current magnitude and red cell dehydration. Baseline KCNN4 activity was increased in HX red cells heterozygous for KCNN4mutant V282M. However, HX red cells maximally stimulated by Ca2+ ionophore A23187 or PMCA Ca2+-ATPase inhibitor orthovanadate displayed paradoxically reduced KCNN4 activity. This reduced Ca2+-stimulated mutant KCNN4 activity in HX red cells was associated with unchanged sensitivity to KCNN4 inhibitor senicapoc and KCNN4 activator Ca2+, with slightly elevated Ca2+ uptake and reduced PMCA activity, and with decreased KCNN4 activation by calpain inhibitor PD150606. The altered intracellular monovalent cation content of HX red cells prompted experimental nystatin manipulation of red cell Na and K contents. Nystatin-mediated reduction of intracellular K+ with corresponding increase in intracellular Na+ in wild type cells to mimic conditions of HX gre...

Source: Am J Physiol Cell Ph... - May 14, 2019 Category: Cytology Authors: Rivera A, Vandorpe DH, Shmukler BE, Andolfo I, Iolascon A, Archer NM, Shabani E, Auerbach M, Hamerschlak N, Morton J, Wohlgemuth JG, Brugnara C, Snyder LM, Alper SL Tags: Am J Physiol Cell Physiol Source Type: research