Abstract
Normal human RBCs have a very low basal permeability (leak) to cations, which is continuously corrected by the Na,K-ATPase. The leak is temperature-dependent, and this temperature dependence has been evaluated in the presence of inhibitors to exclude the activity of the Na,K-ATPase and NaK2Cl transporter. The severity of the RBC cation leak is altered in various conditions, most notably the hereditary stomatocytosis group of conditions. Pedigrees within this group have been classified into distinct phenotypes according to various factors, including the severity and temperature-dependence of the cation leak. As recent breakthroughs have provided more information regarding the molecular basis of hereditary stomatocytosis, it has become clear that these phenotypes elegantly segregate with distinct genetic backgrounds. The cryohydrocytosis phenotype, including South-east Asian Ovalocytosis, results from mutations in SLC4A1, and the very rare condition, stomatin-deficient cryohydrocytosis, is caused by mutations in SLC2A1. Mutations in RHAG cause the very leaky condition over-hydrated stomatocytosis, and mutations in ABCB6 result in familial pseudohyperkalemia. All of the above are large multi-spanning membrane proteins and the mutations may either modify the structure of these proteins, resulting in formation of a cation pore, or otherwise disrupt the membrane to allow unregulated cation movement across the membrane. More recently mutations have been found in two RBC cation channels, PIEZO1 and KCNN4, which result in dehydrated stomatocytosis. These mutations alter the activation and deactivation kinetics of these channels, leading to increased opening and allowing greater cation fluxes than in wild type.
Highlights
At first glance, mature human red blood cells (RBCs) appear to be membranes packed full of hemoglobin, carrying the respiratory gases oxygen and carbon dioxide around the body
The most abundant RBC membrane protein, band 3, exchanges bicarbonate to the plasma in exchange for chloride, a process that is crucial for the efficient transport of carbon dioxide in the blood
Dehydrated hereditary stomatocytosis (DHSt; known as hereditary xerocytosis) is a condition, similar to familial pseudohyperkalemia (FP) that falls at the milder end of the cation leaky spectrum
Summary
Mature human red blood cells (RBCs) appear to be membranes packed full of hemoglobin, carrying the respiratory gases oxygen and carbon dioxide around the body. The non-selective, voltage-dependent cation (NSVDC) channel (Bennekou and Christopherson, 2003) and the K(Na)/H exchanger (Bernhardt and Weiss, 2003) are both activated in low ionic strength conditions and may play a role in cation loss in low chloride media, but probably have little role in cation homeostasis at physiological pH and tonicity Many of these transporters are regulated by changes in cell volume (swelling and/or shrinkage). Evidence from a recent study by Cahalan et al suggests that PIEZO1-mediated calcium influx activates the Gardos channel and triggers cellular dehydration This mechanism has been hypothesized to aid the RBC’s passage through the microvasculature by allowing it to reduce its volume in response to mechanical stimulation or shear stress (Cahalan et al, 2015). It will be interesting to discover whether PIEZO1 is directly involved in regulating other RBC membrane cation transporters that are variously stimulated or inhibited by cell swelling, raising the exciting possibility that PIEZO1 is the master regulator of RBC volume control
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