Molecular Mechanisms of Oxygen-Induced Regulation of Na⁺/K⁺Pump

Abstract

Na⁺/K⁺ pump is deactivated under hypoxic conditions in many cell types, including neurons, cardiac myocytes, hepatocytes, alveolar epithelial cells and chromaffin cells of adrenal medulla (Erecinska and Silver, 2001; Inoue et al 1999; Suzuki et al. 1999; Ziegelhoffer et al. 2000). The ability of the pump to respond to hypoxic conditions with reversible deactivation coupled to a decrease in passive permeability of cell membrane to sodium and potassium preserves cell integrity and ATP levels during prolonged hypoxic periods in hypoxia-tolerant species such as western painted turtle and ground squirrel (Buck & Hochachka, 1993; MacDonald & Storey, 1999). On the other hand, in cells with high passive permeability to inorganic cations deactivation of the pump results in a rapid dissipation of transmembrane gradients, passive accumulation of Na⁺, cell swelling and finally lysis. Rapid decrease in ATP levels, particularly in cells with activemetabolism and ATP production, is believed to be a major course of Na⁺/K⁺ ATPase deactivation under hypoxic conditions (Fig 1). This is clearly true for neurons where ATP depletion under hypoxic conditions occurs within minutes, followed by a decrease in Na⁺/K⁺ pump activity and consequent membrane depolarization, swelling and necrosis. However, deactivation of the pump in response to ischemic hypoxia also occurs in cardiac myocytes where the ATP fuelling the pump is mostly, if not entirely, of glycolytic origin (Ziegelhoffer., 2000). Therefore, along with ATP depletion other mechanisms must be involved in hypoxia-induced deactivation of Na⁺/K⁺ pump. As one such mechanism, it has been suggested that deactivation of Na⁺/K⁺ pump would result from increased production of reactive oxygen species (ROS), because of mitochondrial uncoupling under hypoxic conditions (Chandel et al. 1997; Chandel and Schumacker, 2000; Duranteau et al. 1998), and consecutive oxidation of the pump. However, whereas deactivation of the pump by brief hypoxic treatment is reversible, oxidative treatments cause irreversible inhibition of the pump (Boldyrev and Bulygina, 1997; Dobrota et al. 1999; Ferrari et al. 1991; Huang, Wang and Askari, 1992; Kurella et al. 1997). One more parameter, affected by hypoxia-reoxygenation is cellular redox status, characterised by GSH and GSSG levels.