Evidence for a protective role of the gardos channel againsthemolysis in murine spherocytosis
It has been shown that mice with complete deficiency of all4.1R protein isoforms (4.1[-/-]) exhibit moderate hemolytic anemia, withabnormal erythrocyte morphology (spherocytosis) and decreased membranestability. Here, we characterized the Gardos channel function in vitroand in vivo In erythrocytes of 4.1[-/-]mice. Compared with wild-type,the Gardos channel of 4.1[-/-]erythrocytes showed an Increase in V[max](9.75 +- 1.06 vs 6.08 +- 0.09 mM cell x minute; P<.04) and adecrease in K[m](1.01 +- 0.06 vs 1.47 +- 1.02 mu M; P<.03),indicating an increased sensitivity to activation by intracellularcalcium. In vivo function of the Gardos channel was assessed by the oraladministration of clotrimazole, a well-characterized Gardos channelblocker. Clotrimazole treatment resulted in worsening of anemia andhemolysis, with decreased red cell survival and increased numbers ofcirculating hyperchromic spherocytes and microspherocytes. Clotrimazoleinduced similar changes in 4.2[-/-]and band 3[+/-]mice, indicating thatthese effects of the Gardos channel are shared in different models ofmurine spherocytosis. Thus, potassium and water loss through the Gardoschannelmay play an important protective role in compensating for thereduced surface-membrane area of hereditary spherocytosis (HS)erythrocytes and reducing hemolysis in erythrocytes with cytoskeletalimpairments.
- Research Organization:
- COLLABORATION - U.Verona/Italy
- DOE Contract Number:
- DE-AC02-05CH11231
- OSTI ID:
- 901668
- Report Number(s):
- LBNL-57504; BLOOAW; R&D Project: 862K1A; BnR: 400412000; TRN: US200715%%108
- Journal Information:
- Blood, Vol. 106, Issue 4; Related Information: Journal Publication Date: 2005; ISSN 0006-4971
- Country of Publication:
- United States
- Language:
- English
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