Sensing and responding to hypoxia, molecular and physiological mechanisms

In order to adapt to low oxygen it is necessary first to be able to detect hypoxia, then to initiate the appropriate defense mechanisms. There are two basic detectors: molecular sensors that are directly linked to gene regulation and metabolic indicators that are triggered when the cell goes into a state of energy imbalance. The molecular responses to oxygen deprivation are characterized in a variety of cell types and include activation of oxygen sensors, signaling through specific promoter elements and subsequent downstream adaptations. Many of the components are highly conserved across species. In the brain, the most hypoxic vulnerable of all vertebrate tissues, low oxygen quickly results in a fall in ATP and a consequent increase in adenosine. Both changes act as metabolic indicators of cellular energy crisis and effect mechanisms to reduce metabolic demand. Important lessons on the potential scope of such mechanisms can be provided by the anoxic tolerant turtle brain. Anoxia provokes an early release of adenosine which mediates channel arrest, causes a reduction in K(+) efflux and Ca(2+) influx, and inhibits excitatory neurotransmitter release. There is a differential expression between normoxic and anoxic turtle brains of transcripts encoding the immediate early gene products c-fos and c-jun, the HSP-70 and the apoptosis regulators bcl-2 and bax.