Lutz, P.* L Lutz; Prentice, H.: Sensing and responding to hypoxia, molecular and physiological mechanisms

In order to accommodate to low oxygen it is necessary first to be able to detect hypoxia, then to initiate the appropriate 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 in mammals 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. A fall in ATP acts as a metabolic indicator of cellular energy crisis. In brain, in particular, there is a release of adenosine which acts to reduce metabolic demand. We are investigating the extent to which altered molecular pathways of hypoxia sensing and adaptation may account for the extraordinary ability of the turtle brain to survive prolonged anoxia. Our initial observations show 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. Transcription factor binding assays confirm the presence of a hypoxia response element (HRE) binding activity in anoxic turtle brain and display anoxia regulated binding of the redox dependent factor NF-kappaB. In the anoxic turtle brain an early release of adenosine appears to mediate channel arrest, reducing K+ efflux and Ca2+ influx, and inhibit excitatory neurotransmitter release. The molecular characterisation of hypoxia sensing and adaptation in the turtle brain provides fundamental insights into cell signalling for neuroprotection and neuronal survival in the face of oxygen deprivation.