PF-04691502 Given the estimated number of NSVDC
Given the estimated number of 150–300 NSVDC channels in a red cell  and a single channel conductance of 30 pS at physiological salt concentrations , the maximum conductance observed in intact red PF-04691502 indicate either a very low open state probability, in the order of 10−3 or a far lower unit conductance than observed in the isolated channel. The explanation is not known at present, but given the size of the KCl loss, which can be observed and the changes in estimated membrane potential a fraction of cells close to 1 will participate in the response.
Introduction The transport of oxygen from lungs to tissues and the reverse transport of CO2 are mediated by two specialized molecular structures: hemoglobin and an anion exchange carrier in the red blood cell (RBC) membrane. Encapsulation of ~7.2mmol of impermeable hemoglobin per liter of intracellular water in a cell moving within a plasma environment that has a much lower protein concentration creates a huge osmotic pressure. However, as explicitly formulated in the “pump-leak” concept , the risk of colloid-osmotic swelling and bursting is prevented by a very low membrane permeability to cations, allowing the pumps Na+/K+-ATPase and Ca2+-ATPase to extrude the residual Na+ and Ca2+ leaks at minimal metabolic cost. Anion movements through the RBC membrane are essentially linked to the respiratory function: a million copies of electroneutral Cl−/HCO3− exchanger per cell allow 85% of the CO2 produced in the tissues to be transported in the blood as HCO3− ions; one hundred copies of anion channels, allowing conductive permeation, clamp the RBC membrane potential (Em) at the equilibrium potential for Cl− ions (ECl), thereby permitting the exchangers to work optimally in absence of electro-chemical gradients for anions movements. The molecular nature of these anion channels is still unknown and, under steady-state, their activity remains negligible which is in accord with the estimates of the whole-cell conductance in normal un-stimulated cells, i.e. about 70 picoSiemens (pS)  and the 40–50pS calculated from the suspension experiments . It appears from this picture that there is very little room for ionic channel activity in the maintenance of RBC homeostasis. However, it is known that the red cell membrane is endowed with a large variety of cation channels , , , ,  and anion channels , , , , , ,  activable under experimental conditions where they can potentially give very high single cell conductances capable to threaten homeostasis. These channels are usually dormant but have been shown to be active in some pathological situations. What does this mean? Could there be physiological conditions under which the red cell needs to activate these high conductances, or are the channels relics of a past function susceptible to be re-activated by pathogens?
Gardos channels Among these conductive pathways, 100–200 copies of Ca2+ sensitive K+ channel, also called “Gardos” channel  or IK1, are expressed in human RBC membrane , , , . These channels are activated by Ca2+ ions interacting with calmodulin when intracellular Ca2+ level is increased from a physiological level of 20–50nmol l−1 to above a threshold of 150nmol l−1 , , maximal activation being obtained around 2μmol l−1. Under physiological conditions, a full experimental activation of Gardos channels induces massive outward K+ flux and membrane hyperpolarization . The sudden shift of Em from ECl toward the equilibrium potential for K+ ions (EK) creates a driving force for anion extrusion through conductive permeation pathways , , , , . The water loss accompanying the parallel exit of K+ ions and anions results in dramatic dehydration. When induced experimentally, the extent of this process is totally dependent on the membrane conductive permeability for anions (PGA) and the K+ efflux from the red cells shows a marked dependence on the nature of the anion present in the suspending medium. This explains why SCN− or NO3− ions, more permeant than Cl−, were frequently used to by-pass any rate-limiting effects of anion permeability . Thus, the rate of dehydration by Gardos channel activation is determined upstream by the magnitude of Ca2+ entry and downstream by the ability of conductive pathways to facilitate anion efflux. The Gardos channel is inactive in the “resting cell” and its physiological role in vivo, if any, is still unknown. A major task for the future will be to address this issue in healthy cells; a pathophysiological role is already known in sickle cell anemia  but the precise mechanism of its contribution remains unclear.