Disruption of the Gardos channel (KCa3.1) in mice causes subtle erythrocyte macrocytosis and progressive splenomegaly

• Published in: Pflügers Archiv Vol. 458; no. 2; pp. 291 - 302
• Main Authors: Grgic, Ivica, Kaistha, Brajesh P., Paschen, Steffen, Kaistha, Anuradha, Busch, Christoph, Si, Han, Köhler, Kernt, Elsässer, Hans-Peter, Hoyer, Joachim, Köhler, Ralf
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-06-2009; Springer Nature B.V
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell Death - drug effects; Cell Size; Erythrocyte Count; Erythrocyte Deformability - drug effects; Erythrocyte Indices - drug effects; Erythrocytes; Flow Cytometry; Human Physiology; Intermediate-Conductance Calcium-Activated Potassium Channels - deficiency; Intermediate-Conductance Calcium-Activated Potassium Channels - physiology; Ion Channels; Iron - metabolism; Mice; Molecular Medicine; Neurosciences; Pyrazoles - pharmacology; Receptors; Receptors and Transporters; Splenomegaly - etiology; Splenomegaly; Erythrocytes; Filterability; Transgenic mouse; Ca; activated potassium channel; Osmotic stress
• ISSN: 0031-6768; 1432-2013
• DOI: 10.1007/s00424-008-0619-x

Gardos channel, the erythrocyte Ca
2+
-activated K
+
channel (K
Ca
3.1), is considered a major regulator of red blood cell (RBC) volume by mediating efflux of potassium and thus cell dehydration and shrinkage. However, the functional importance of K
Ca
3.1 in RBC in vivo is incompletely understood. Here, we used K
Ca
3.1
−/−
-mice to investigate the consequences of K
Ca
3.1 deficiency for RBC indices, functions, and sequestration. RBCs of K
Ca
3.1
−/−
-mice of all ages were mildly macrocytic but their biconcave appearance being preserved. RBC number, total hemoglobin, and hematocrit were unchanged in the adult K
Ca
3.1
−/−
-mice and increased in the premature K
Ca
3.1
−/−
-mice. Filterability, Ca
2+
-dependent volume decrease and osmotic tolerance of RBCs lacking K
Ca
3.1 were noticeably reduced when compared to RBC of wild-type littermates. Deformability to increasing shear stress was unchanged. Strikingly, K
Ca
3.1
−/−
-mice developed progressive splenomegaly which was considerable (∼200% of controls) in the >6-month-old mice and was paralleled by increased iron deposition in the aged mice presumably as a consequence of enhanced RBC sequestration. Daily injections of the K
Ca
3.1-blocker TRAM-34 (120 mg/kg) also produced mild splenomegaly in wild-type mice. We conclude that genetic deficit of erythroid K
Ca
3.1 causes mild RBC macrocytosis, presumably leading to reduced filterability, and impairs volume regulation. These RBC defects result in mild but progressive splenomegaly.