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Am J Physiol Cell Physiol. 2019 May 15. doi: 10.1152/ajpcell.00074.2019. [Epub ahead of print]

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

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Departments of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, United States.
Department of Molecular Medicine and Medical Biotechnologies, "Federico II" University of Naples, Italy CEINGE, Biotecnologie Avanzate, Naples, Italy.
Division of Hematology and Oncology, Boston Children's Hospital; Dana- Farber Cancer Center; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, United States.
Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02215, United States.
5233 King Ave #308, Rosedale, MD 21237, United States.
Department of Hematology, Hospital Israelita Albert Einstein, Sao Paulo, SP, Brazil.
Quest Diagnostics, San Juan Capistrano, CA 92675, United States.
Department of Laboratory Medicine, Boston Children's Hospital and Department of Pathology, Harvard Medical School, Boston, MA 02215, United States.
Quest Diagnostics, Marlborough, MA 01752. Departments of Medicine and Laboratory Medicine, University of Massachusetts Medical Center, Worcester, MA 01655, United States.
Departments of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215. Broad Institute of Harvard and MIT, Cambridge MA 02139, United States.


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 greatly suppressed vanadate-stimulated and A23187-stimulated KCNN4 activity in those wild type cells. However, conferral of wild type cation contents on HX red cells failed to restore wild type stimulated KCNN4 activity to those HX cells. The phenotype of reduced maximally stimulated KCNN4 activity was shared by HX erythrocytes expressing heterozygous PIEZO1 mutants R2488Q and V598M, but not by HX erythrocytes expressing heterozygous KCNN4 mutant R352H or PIEZO1 mutant R2456H. Our data suggest that chronic KCNN4-driven red celldehydration and intracellular cation imbalance can lead to functional inactivation of KCNN4 activity in HX and wild type red cells.


dehydrated stomatocytosis; ionophore; potassium channel; red blood cell; senicapoc


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