Involvement of potassium channel in AQP1-mediated water and gas transport in erythrocytes

Abstract

Elevated plasma cholesterol affects nearly 100 million Americans, a third of the US population, resulting in devastating health consequences and nearly one million deaths annually. Although the long-term effect of elevated plasma cholesterol is known for its accretion in arterial walls, little was understood of its immediate effects until recently (Jena and Lee, 2010). Cholesterol in blood plasma is known to rapidly enter and incorporate into the red blood cell (RBC) plasma membrane (Tall, 1993; Glomset et al., 1995; Ishizake et al., 1994). As early as the 1970s, it was demonstrated in human studies that blood plasma and RBC membrane cholesterol levels are inversely associated with the transmembrane O2 diffusion rate of RBC (Steinbach et al., 1974): as cholesterol levels in the blood plasma and consequently in the RBC membrane decrease, O2 diffusion in RBC increases (Steinbach et al., 1974; Menchaca et al., 2004). Then in 2010 (Jena and Lee, 2010), we reported for the first time that the immediate effect of elevated plasma cholesterol is dysfunction of active water and CO2 transport via the AQP1 channel through the RBC membrane. The effect of the phospholipase A2 (PLA2) inhibitor ONO-RS-082 (ONO) on ameliorating the detrimental effects of cholesterol was further demonstrated from that study (Jena and Lee, 2010). In the past decade, the tetradecapeptide wasp venom mastoparan, GTP, the GTP-binding heterotrimeric Gαi/ Gαo proteins, vH +-ATPase, PLA2, the K+ and Cl– channels, and aquaporins (Abu-Hamdah et al., 2004), have been implicated in the gating of water into secretory vesicles. A similar mechanism operating at the RBC membrane is therefore hypothesized. Gαi3 has been implicated in various tissues to regulate both K+ and Cl– ion channels at the plasma membrane (Delport et al., 1997; Knepper and Inoue, 1994, 1997). PLA2 has also been found to regulate both K+ and Cl– ion channels. Since Gαi3 and PLA2 are present at the RBC membrane (Mukherjee and Maxfield, 2004; Hillman et al., 2005), I hypothesize the involvement of both Gαi3 and PLA2 in the regulation of AQP1 activity. Furthermore, since K+ and Cl– ion channels are present at the RBC membrane (Hillman et al., 2005), the involvement of Gαi3 in the regulation of K+ and Cl– ion channels at the RBC membrane and its possible implication for AQP1-mediated water entry were investigated. Results from my studies demonstrate that K+ and Cl– ion channels are associated with AQP1 at the RBC membrane, and that the K+ channel inhibitor Glyburide currently used in treating diabetes reverses the detrimental effects of cholesterol on RBC function. Involvement of potassium channel in AQP1-mediated water and gas transport in erythrocytes Siddhartha G. Jena*