Oxygen sensing by ion channels

Oxygen is required for the survival of all higher life forms due to its role in mitochondrial respiration permitting ATP synthesis by oxidative phosphorylation. Oxygen is also necessary for many other cellular functions, including the synthesis of steroid hormones or the generation of reactive oxygen species in the macrophage defense response. In mammals, 02 diffuses into the blood in the lungs, is concentrated within the erythrocytes by its binding to hemoglobin and is distributed throughout the body by the circulatory system. Arterial and tissular 02 tension (P02) are kept within restricted limits by shortand long-term adaptative mechanisms set in motion by changes in 07 availability due to environmental or physiological circumstances. An immediate response to a hypoxic stress is the reflex increase in respiratory rate resulting from the activation of arterial 02 chemoreceptors. In these organs, decrements in arterial P02 are translated into afferent nerve discharges stimulating the brain stem respiratory centers to produce hyperventilation [1, 2]. Acute regional hypoxia also produces vasorelaxation of most systemic arteries in an effort to increase 02 delivery to hypoxic tissues, whereas it constricts pulmonary resistance arteries, thereby diverting blood toward the better ventilated alveoli [3, 4]. Besides the rapid functional adaptations to hypoxia, protracted alterations in 02 availability also lead to changes in the expression of genes encoding for various hormones, enzymes, and growth factors [5—8]. One of the best known examples is the enhancement of the synthesis and secretion of erythropoietin by the kidney and liver in response to chronic hypoxemia, which increases the 02-carrying capacity of the blood by augmenting the production of red blood cells [9]. Despite the paramount importance of the physiologic functions regulated by 02 tension the molecular and cellular processes underlying the oxygen-dependent control systems are largely unknown. With the exception of the recently identified hemoprotein involved in bacteria N2 fixation [10], the nature of the 02 sensors is still an enigma. In the past few years it has been demonstrated that ion channels represent novel molecular entities participating in 02 chemoreception. It has been shown that the activity of various kinds of voltage-gated ion channels can be modulated by 02 and that these channels might play a key role in several cellular responses to hypoxia.