Cellular Mechanism of Oxygen Sensing

Abstract

O2 sensing is a fundamental biological process necessary for adaptation of living organisms to variable habitats and physiological situations. Cellular responses to hypoxia can be acute or chronic. Acute responses rely mainly on O2-regulated ion channels, which mediate adaptive changes in cell excitability, contractility, and secretory activity. Chronic responses depend on the modulation of hypoxia-inducible transcription factors, which determine the expression of numerous genes encoding enzymes, transporters and growth factors. O2-regulated ion channels and transcription factors are part of a widely operating signaling system that helps provide sufficient O2 to the tissues and protect the cells against damage due to O2 deficiency. Despite recent advances in the molecular characterization of O2-regulated ion channels and hypoxia-inducible factors, several unanswered questions remain regarding the nature of the O2 sensor molecules and the mechanisms of interaction between the sensors and the effectors. Current models of O2 sensing are based on either a heme protein capable of reversibly binding O2 or the production of oxygen reactive species by NAD(P)H oxidases and mitochondria. Complete molecular characterization of the hypoxia signaling pathways will help elucidate the differential sensitivity to hypoxia of the various cell types and the gradation of the cellular responses to variable levels of PO2. A deeper understanding of the cellular mechanisms of O2 sensing will facilitate the development of new pharmacological tools effective in the treatment of diseases such as stroke or myocardial ischemia caused by localized deficits of O2.

A neuroglobin-overexpressing transgenic mouse

“…Two major classes of hypoxia signaling pathways are activated: fast (seconds to minutes) responses mediated through O 2 -sensitive ion channels and slow (hours to days) responses that involve transcriptional activation of hypoxia-inducible genes (Lopez-Barneo et al, 2001). In mammalian forebrain neurons, for example, fast responses to hypoxia lead to hyperpolarization by activating K Ca and K ATP currents and reducing voltage-gated Na currents (Lopez-Barneo et al, 2001). The best characterized slow responses are those orchestrated through the basic helix-loop-helix Per-Arnt-Sim transcription factor, HIF-1.…”

Hypoxia Inducible Factor-2α Stabilization and Maxi-K + Channel β 1 -Subunit Gene Repression by Hypoxia in Cardiac Myocytes

“…We have shown that it occurs at the transcriptional level and is mimicked by DMOG and cobalt, inhibitors of prolyl hydroxylases. 24,[35][36][37] Hypoxic regulation of the ␤ 1 gene is independent of membrane depolarization and extracellular Ca 2ϩ influx. The maxi-K ␤ 1 -subunit mRNA expression is also decreased by the application of hydrogen peroxide, an observation fully compatible with the notion that production of reactive oxygen species in mitochondria during hypoxia is required for effective inhibition of prolyl hydroxylases and subsequent stabilization of Hif proteins.…”

Reactive oxygen species and cellular oxygen sensing

“…From an intuitive standpoint, one might assume that ROS levels drop during hypoxia since ROS require O 2 as a substrate for their production and several studies support this prediction. For instance, it has been shown that endothelial cell plasma membranes release less extracellular H 2 O 2 under hypoxia compared to normoxia [64,65]. In addition, perinuclear endoplasmic reticulum (ER) generation of OH, presumably derived from the "Fenton reaction" of H 2 O 2 with transition metals, is higher under normoxic conditions compared to hypoxia [66].…”