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The Journal of Experimental Biology 205, 3579-3586 (2002)
Copyright © 2002 The Company of Biologists Limited

Commentary

Adaptive responses of vertebrate neurons to hypoxia

Philip E. Bickler^1,* and Paul H. Donohoe²

¹ Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143-0542 USA
² Department of Physiology, University of Otago, Dunedin, New Zealand

^* Author for correspondence (e-mail: BicklerP{at}anesthesia.ucsf.edu)

Accepted 23 August 2002

The damage caused to mammalian neurons during ischaemic events in the brain (e.g. following a stroke), is an area of major interest to neuroscientists. The neurons of hypoxia-tolerant vertebrates offer unique models for identifying new strategies to enhance the survival of hypoxia-vulnerable neurons. In this review, we describe recent advances in our understanding of how hypoxia-tolerant neurons detect decreases in oxygen and create signals that have immediate and long-term effects on cell function and survival. Sensing and adapting to low oxygen tension involves numerous modalities with different times of activation and effect. Sensors include membrane proteins such as ionotropic ion channels, membrane or cytosolic heme proteins, mitochondrial proteins and/or oxygen sensitive transcription factors such as HIF-1 and NFB. Signaling molecules involved in O₂ sensing include mitogen-activated protein kinases, ions such as Ca²⁺ and metabolites such as adenosine. These signals act rapidly to reduce the conductance of ion channels (ion flux arrest) and production of energy (metabolic arrest), and slowly to activate specific genes. The ability to construct an energy budget, illustrating which physiological processes are depressed during both long-term and acute metabolic suppression in hypoxia-tolerant neurons, would be of significant value in devising new strategies for neuroprotection. Additionally it is not known how metabolism is regulated at `pilot-light' levels at which energy-producing and energy-consuming processes are balanced. The regulation of organelle and cell fate during long-term hypoxia is almost completely unexplored, and whether programmed cell death and regeneration of lost neurons occur following protracted dormancy is also of considerable interest.

Key words: neuron, hypoxia, oxygen sensor, intracellular calcium, vertebrate

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