In our previous studies in intact red cells we seldom observed spontaneous channel activity in cell attached patches when the cells were bathed in Lafutidine physiological saline solution. Episodically though, we did detect transient activity immediately following seal formation, but only when contact was facilitated by underpressure. Intrigued by the systematic link between the negative pressure pulse and the transient current response, we explored some of the medium requirements in preliminary experiments. It soon became clear that the presence of Ca2+ in the bathing medium was essential for the transient current response. The association between red cell membrane deformation and changes in membrane permeability affecting Ca2+ and other ions has been documented for a number of physiological and pathological processes in the past, based mostly on experimentation with red blood cell suspensions. Physiological shear stress in the circulation has been claimed to cause a reversible increase in Ca2+ permeability. Recent evidence supported the view that the increasing density of aging human RBCs, attributed to a progressive loss of KCl and osmotic water, results from the cumulative effects of declining Ca2+ extrusion capacity of the plasma membrane Ca2+ pump, aided by minor episodes of increased Ca2+ permeability in the circulation. In sickle cell anemia, deoxygenation of red blood cells in the circulation Riboflavin reversibly increases their membrane permeability to Na +,K +, Ca 2+ and Mg2+, and this increase has been attributed to the activation of Psickle, a poorly selective cation permeability pathway thought to be generated by the protruding deformation of the RBC membrane on contact with polymers of deoxy-hemoglobin S. The increase in i resulting from Psickle activation in turn activates the Ca2+sensitive K + channel of the red cell membrane a critical stage in the mechanism of sickle cell dehydration. A localized increase in red cell Ca2+ associated with local dynamic membrane deformations was also suggested to be involved in the process of apical alignment of malaria merozoites, just before invasion.