Functional significance of the intermediate conductance Ca2+-activated K+ channel for the short-term survival of injured erythrocytes

• Published in: Pflügers Archiv Vol. 460; no. 6; pp. 1029 - 1044
• Main Authors: Föller, Michael, Bobbala, Diwakar, Koka, Saisudha, Boini, Krishna M., Mahmud, Hasan, Kasinathan, Ravi S., Shumilina, Ekaterina, Amann, Kerstin, Beranek, Golo, Sausbier, Ulrike, Ruth, Peter, Sausbier, Matthias, Lang, Florian, Huber, Stephan M.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.11.2010
• Subjects: Anemia, Hemolytic - chemically induced; Animals; Bacterial Toxins - pharmacology; Biomedical and Life Sciences; Biomedicine; Calcium - blood; Cell Biology; Erythrocytes - drug effects; Erythrocytes - physiology; Female; Hemolysin Proteins - pharmacology; Hemolysis - drug effects; Human Physiology; Intermediate-Conductance Calcium-Activated Potassium Channels - deficiency; Intermediate-Conductance Calcium-Activated Potassium Channels - physiology; Ion Channels; Malaria - blood; Malaria - pathology; Male; Mice; Molecular Medicine; Neurosciences; Phenylhydrazines - pharmacology; Plasmodium berghei - pathogenicity; Receptors; Receptors and Transporters; Staphylococcus aureus; Suicidal erythrocyte death; Calcium signaling; Intermediate conductance Ca; 3.1; Red blood cell; Scramblase; channel K; activated K
• ISSN: 0031-6768; 1432-2013
• DOI: 10.1007/s00424-010-0878-1

Increased cytosolic Ca 2+ concentrations activate Gardos K + channels in human erythrocytes with membrane hyperpolarization, efflux of K + , Cl − , and osmotically obliged H 2 O resulting in cell shrinkage, a phenomenon referred to as Gardos effect. We tested whether the Gardos effect delays colloid osmotic hemolysis of injured erythrocytes from mice lacking the Ca 2+ -activated K + channel K Ca 3.1. To this end, we applied patch clamp and flow cytometry and determined in vitro as well as in vivo hemolysis. As a result, erythrocytes from K Ca 3.1-deficient (K Ca 3.1 −/− ) mice lacked Gardos channel activity and the Gardos effect. Blood parameters, reticulocyte count, or osmotic erythrocyte resistance, however, did not differ between K Ca 3.1 −/− mice and their wild-type littermates, suggesting low or absent Gardos channel activity in unstressed erythrocytes. Oxidative stress-induced Ca 2+ entry and phospholipid scrambling were significantly less pronounced in K Ca 3.1 −/− than in wild-type erythrocytes. Moreover, in vitro treatment with α-toxin from Staphylococcus aureus , which forms pores in the cellular membrane, resulted in significantly stronger hemolysis of K Ca 3.1 −/− than of wild-type erythrocytes. Intravenous injection of α-toxin induced more profound hemolysis in K Ca 3.1 −/− than in wild-type mice. Similarly, intra-peritoneal application of the redox-active substance phenylhydrazine, an agent for the induction of hemolytic anemia, was followed by a significantly stronger decrease of hematocrit in K Ca 3.1 −/− than in wild-type mice. Finally, malaria infection triggered the activation of K Ca 3.1 and transient shrinkage of the infected erythrocytes. In conclusion, K Ca 3.1 channel activity and Gardos effect counteract hemolysis of injured erythrocytes, thus decreasing hemoglobin release into circulating blood.