O-2 sensing is a fundamental biological process necessary for adaptation of
living organisms to variable habitats and physiological situations. Cellul
ar responses to hypoxia can be acute or chronic. Acute responses rely mainl
y on O-2-regulated ion channels, which mediate adaptive changes in cell exc
itability, contractility, and secretory activity. Chronic responses depend
on the modulation of hypoxia-inducible transcription factors, which determi
ne the expression of numerous genes encoding enzymes, transporters and grow
th factors. O-2-regulated ion channels and transcription factors are part o
f a widely operating signaling system that helps provide sufficient O-2 to
the tissues and protect the cells against damage due to O-2 deficiency. Des
pite recent advances in the molecular characterization of O-2-regulated ion
channels and hypoxia-inducible factors, several unanswered questions remai
n regarding the nature of the O-2 sensor molecules and the mechanisms of in
teraction between the sensors and the effectors. Current models of O-2 sens
ing are based on either a heme protein capable of reversibly binding O-2 or
the production of oxygen reactive species by NAD(P)H oxidases and mitochon
dria. 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 O-2 sensing wi
ll facilitate the development of new pharmacological tools effective in the
treatment of diseases such as stroke or myocardial ischemia caused by loca
lized deficits of O-2.