Jens Georg Leipziger

Escherichia coli α-hemolysin triggers shrinkage of erythrocytes via KCa3.1 and TMEM16A channels with subsequent phosphatidylserine exposure

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α-Hemolysin from Escherichia coli (HlyA) readily lyse erythrocytes from various species. We have recently demonstrated that this pore-forming toxin provokes distinct shrinkage and crenation before it finally leads to swelling and lysis of erythrocytes. The present study documents the underlying mechanism for this severe volume reduction. We show that HlyA-induced shrinkage and crenation of human erythrocytes occur subsequent to a significant rise in [Ca2+]i. The Ca2+-activated K+ channel K Ca3.1 (or Gardos channel) is essential for the initial shrinkage, because both clotrimazole andTRAM-34prevent the shrinkage and potentiate hemolysis produced by HlyA. Notably, the recently described Ca 2+-activated Cl- channel TMEM16A contributes substantially to HlyA-induced cell volume reduction. Erythrocytes isolated from TMEM16A -/- mice showed significantly attenuated crenation and increased lysis compared with controls. Additionally, we found that HlyA leads to acute exposure of phosphatidylserine in the outer leaflet of the plasma membrane. This exposure was considerably reduced by KCa3.1 antagonists. In conclusion, this study shows that HlyA triggers acute erythrocyte shrinkage, which depends on Ca2+-activated efflux of K+ via K Ca3.1 and Cl- via TMEM16A, with subsequent phosphatidylserine exposure. This mechanism might potentially allow HlyA-damaged erythrocytes to be removed from the bloodstream by macrophages and thereby reduce the risk of intravascular hemolysis.

Original languageEnglish
JournalJournal of Biological Chemistry
Pages (from-to)15557-15565
Number of pages9
Publication statusPublished - 14 May 2010

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