The conductance of red blood cells from sickle cell patients: ion selectivity and inhibitors
- 3 April 2012
- journal article
- research article
- Published by Wiley in The Journal of Physiology
- Vol. 590 (9), 2095-2105
- https://doi.org/10.1113/jphysiol.2012.229609
Abstract
The abnormally high cation permeability in red blood cells (RBCs) from patients with sickle cell disease (SCD) occupies a central role in pathogenesis. Sickle RBC properties are notably heterogeneous, however, thus limiting conventional flux techniques that necessarily average out the behaviour of millions of cells. Here we use the whole-cell patch configuration to characterise the permeability of single RBCs from patients with SCD in more detail. A non-specific cation conductance was reversibly induced upon deoxygenation and was permeable to both univalent (Na+, K+, Rb+) and also divalent (Ca2+, Mg2+) cations. It was sensitive to the tarantula spider toxin GsMTx-4. Mn2+ caused partial, reversible inhibition. The aromatic aldehyde o-vanillin also irreversibly inhibited the deoxygenation-induced conductance, partially at 1mM and almost completely at 5mM. Nifedipine, amiloride and ethylisopropylamiloride were ineffective. In oxygenated RBCs, the current was pH sensitive showing a marked increase as pH fell from 7.4 to 6, with no change apparent when pH was raised from 7.4 to 8. The effects of acidification and deoxygenation together were not additive. Many features of this deoxygenation-induced conductance (non-specificity for cations, permeability toCa(2+) andMg(2+), pH sensitivity, reversibility, partial inhibition by DIDS and Mn2+) are shared with the flux pathway sometimes referred to as Psickle. Sensitivity to GsMTx-4 indicates its possible identity as a stretch-activated channel. Sensitivity to o-vanillin implies that activation requires HbS polymerisation but since the conductance was observed in whole-cell patches, results suggest that bulk intracellular Hb is not involved; rather a membrane-bound subfraction is responsible for channel activation. The ability to record Psickle-like activity in single RBCs will facilitate further studies and eventual molecular identification of the pathway involved.This publication has 50 references indexed in Scilit:
- Cation Channels in Erythrocytes - Historical and Future PerspectiveThe Open Biology Journal, 2011
- What Noseleaves Do for FM Bats Depends on Their Degree of Sensorial SpecializationPLOS ONE, 2010
- Hypoxia Activates a Ca2+-Permeable Cation Conductance Sensitive to Carbon Monoxide and to GsMTx-4 in Human and Mouse Sickle ErythrocytesPLOS ONE, 2010
- TRPC3 Activation by Erythropoietin Is Modulated by TRPC6Published by Elsevier BV ,2009
- Mechanosensitive ion channels and the peptide inhibitor GsMTx-4: History, properties, mechanisms and pharmacologyToxicon, 2007
- The effect of deoxygenation on whole-cell conductance of red blood cells from healthy individuals and patients with sickle cell diseaseBlood, 2006
- Oxygen sensitivity of red cell membrane transporters revisitedBioelectrochemistry, 2004
- Simultaneous Determination of Low Free Mg2+ and pH in Human Sickle Cells using 31P NMR SpectroscopyPublished by Elsevier BV ,2002
- Nitrendipine is a potent inhibitor of the Ca2+‐activated K+ channel of human erythrocytesFEBS Letters, 1992
- The function of calcium in the potassium permeability of human erythrocytesBiochimica et Biophysica Acta, 1958