Key contributions of the Na / H exchanger subunit 1 and HCO 3 transporters in regulating neuronal cell fate in prolonged hypoxia Howard

HCO3 TRANSPORTERS and the Na /H exchanger (NHE) contribute in a major way to maintenance of ionic and pH homeostasis in neurons. The study by Xue et al. (17) demonstrates that, in prolonged neuronal hypoxia, inhibition of HCO3 transporters by DIDS is protective and inhibition of NHE by either HOE 643 or T-162559 results in increased cell death. These observations have important implications for potential therapeutic interventions that could target upregulation of NHE activity in diseases marked by prolonged hypoxia. The protective role of NHE function in prolonged hypoxia contrasts markedly with a prosurvival response of NHE inhibition in certain models of myocardial ischemia or brain ischemia. This editorial focus includes a discussion of the data on NHE and HCO3 transporter inhibition in hypoxic neurons and in addition considers the differential contributions to cell fate decisions in hypoxia of mild or severe acidosis. In brain ischemia, for example, acidosis may contribute to neuronal death through elevations in oxidative stress, key modifications in prodeath signaling proteins, or potentially though increased intracellular Na and subsequent Ca overload. Elevated reactive oxygen species (ROS) is known to be a major contributor to neuronal adaptations associated with chronic intermittent hypoxia. Chronic continuous hypoxia, by contrast, is not generally associated with ROS signaling, but interestingly some recent evidence points to some specific signaling roles for ROS in prolonged hypoxia, perhaps via hypoxia-inducible factor (HIF)-1. In chronic continuous hypoxia, in vivo, specific HCO3 transporters have been reported to be downregulated in brain perhaps as part of an energy-saving cellular survival response. The detrimental effects of inhibition of the NHE and the protective effects of inhibiting HCO3 transporters in prolonged neuronal hypoxia emphasize the critical importance of ionic and pH homeostasis in maintaining neuronal function and may lead to more comprehensive understanding of the role of pH balance in proapoptotic and prosurvival signaling. While the mammalian brain does have some capability for depressing its metabolism upon oxygen deprivation, such protective mechanisms are known to fail readily in brain ischemia, leading to a series of events that are catastrophic for neurons, including ATP loss, membrane depolarization, and an uncontrolled release of excitatory neurotransmitters (12). Hypoxic injury in neurons is closely linked to a substantial Ca overload that plays a central role in excitotoxic cell death (18). In brain tissue, hypoxia induces complex changes in extracellular and intracellular pH, and, under ischemic conditions, numerous studies report a decrease in intracellular pH. Cerebral ischemia is associated with metabolite build-up, resulting in a fall in both neuronal and glial pHi that may frequently render these cells more prone to injury. Central neurons are thus extremely sensitive to oxygen deprivation, and resulting alterations in ionic and pHi homeostasis may elicit cell injury and death. The article by Xue et al. (17) provides important insights into the effects of hypoxia and acidosis on neurons in culture. This investigation demonstrates a prosurvival role for the NHE and a prodeath role for HCO3 transporters under conditions of prolonged hypoxic exposure.