Submitted November 13, 2006
Accepted April 10, 2007
Effects of age-dependent membrane transport changes on the homeostasis of senescent human red blood cells
Virgilio L. Lew*, Nuala Daw, Zipora Etzion, Teresa Tiffert, Adaeze Muoma, Laura Vanagas, and Robert M. Bookchin
Dept of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
Dept of Medicine, Albert Einstein College of Medicine, New York, NY, United States
* Corresponding author; email: vll1{at}cam.ac.uk.
Little is known about age-related changes in RBC membrane transport and homeostasis. We investigated first whether the known large variation in plasma membrane Ca2+ pump (PMCA) activity was correlated with RBC age. Glycated hemoglobin, Hb A1c, was used as a reliable age marker for normal RBCs. We found an inverse correlation between PMCA strength and Hb A1c content, indicating that PMCA activity declines monotonically with RBC age. The previously described subpopulation of high-Na+, low-density RBCs had the highest Hb A1c levels, suggesting it represents a late homeostatic condition of senescent RBCs. Thus, the normal densification process of RBCs with age must undergo late reversal, requiring a membrane permeability increase with net NaCl gain exceeding KCl loss. Activation of Pcat, a non-selective cation channel, was considered the key link in this density-reversal. Investigation of Pcat properties showed that its most powerful activator was increased intracellular Ca2+. Pcat was comparably selective to Na+, K+, choline and N-methyl-D-glucamine, indicating a fairly large, poorly selective cation permeability pathway. Based on these observations, a working hypothesis is proposed to explain the mechanism of progressive RBC densification with age and of the late reversal to a low-density condition with altered ionic gradients.
