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  • br A small conductance chloride channel SCC In


    A small conductance chloride channel (SCC) In addition to the above-described channels, a 5pS SCC has been encountered in electrophysiological recordings. This channel, exhibiting long periods of opening separated by long intervals of closing, showed the same characteristics as the SCC described in previous studies of Plasmodium falciparum-infected VRT752271 [9], [43]. This Zn2+-sensitive channel might belong to the ClC-2 family of chloride channels, as suggested by expression of ClC-2 proteins detected on immunoblots [66]. This SCC might contribute to the basal anionic conductance clamping the RBC membrane potential and be involved in RBC volume regulation since ClC-2 channels are activated in volume-challenged cells.
    Involvement in physiological and pathophysiological situations As previously stated, Gardos channels are usually dormant, but intense activity has been reported or suspected in some pathological situations. In the same way, Ca2+ pathways, cationic non-selective pathways, and large poorly selective anion channel with a selectivity SCN>I>Br>Cl>acetate>lactate>glutamate allowing organic and inorganic cations to pass, are not directly involved in RBC homeostasis but are susceptible of activation in specific physiological and pathophysiological situations such as senescence [67], sickle cell anemia [28] and malaria [68], [69]. These situations have been very well documented but a mechanistic understanding of complex electrophysiological events underlying ion transports is still lacking. A PBR/VDAC, able to function in different functional states of varying cation or anion selectivity, could account for a number of different physiological and pathophysiological conditions documented in human RBCs, the most relevant of which are:
    A unifying hypothesis That most or all processes discussed here may be mediated by a single transporter is a tempting unifying hypothesis. There is now substantial evidence, based on electrophysiological measurements and molecular biology, that VDAC may be a prime candidate for such a role. The calcium permeability pathway PCa is clearly the first link of the chain when induced by membrane deformation as shown in shear stress or sickling. Although detected indirectly as a Ca2+ pathway through its activating effects on Gardos channels, it may actually reflect a particular functional state of a VDAC channel, or permeation through any other protein of the PBR complex, or passive diffusion through stretched RBC membrane. PCa's role has been clearly evidenced in SS cells and is considered a good candidate to account for periodic Ca2+ influx resulting from shear-stress-induced membrane deformations in the microcirculation. Concerning malaria, PCa's participation in the activation of NPP is still unclear. The second link of the chain is the Gardos channel, which has the potential to induce either fast dehydration as evidenced in sickle cell anemia or slow dehydration resulting from periodic and brief Ca2+ influx as suspected in cell aging. Whatever its physiological or pathological origin, increasing density is associated with a fall in cell water content, hyperpolarization, cell acidification, increase in [Ca2+]i, variations in redox status and modified interactions with elements of the cytoskeleton. The question then is whether any of these changes in homeostatic variables can influence a VDAC channel to switch from an inactive mode (or simply PCa mode) to the cationic non-selective functional mode. Concerning a further switch from NSC mode to the large conductance anionic mode of the VDAC channel, it seems that it can only be expected in P. falciparum-infected cells since NPP render infected cells vulnerable to rapid lysis in isotonic alanine or sorbitol media, a phenomenon not reproduced in any other VDAC-suspected participation. At this point it is important to mention three studies using the patch-clamp technique, reporting on the existence of a voltage-gated non-selective cation channel which opens at high positive and negative potentials [6], [7], [79]. These studies might constitute an early description of the RBC VDAC functioning in its NSC mode.