Fig. 1. Oxygen signaling in neurons. Rapid responses to hypoxia are shown in red and more slowly developing responses are shown in blue. (+) indicates a potentiating effect on the target, (-) an inhibitory one. Oxygen interacts with a variety of target molecules, both at the cell surface, e.g. ion channels (see Table 1), NADPH oxidase (Prabhakar and Overholt, 2000), cytosol, e.g. HIF and related proteins (Semenza, 1999), and organelles such as mitochondria. Decreases in oxygen tension have direct effects on some ion channels (e.g. potassium channels, see references in Table 1) and on molecules associated with transcription factors such as HIF-1. Hypoxia has indirect effects mediated by changes in the bioenergetic state of mitochondria via intermediate signaling modalities such as Ca²⁺ (Berridge et al., 2000; Bickler et al., 2000) and reactive oxygen species (ROS) (Haddad and Land, 2000). Growth factors (Nicole et al., 2001), cytokines and inorganic ions (Millhorn et al., 2000) may also modulate neuronal responses to hypoxia. Many of these signals converge on MAP kinase cassettes including the ERK, JNK and p38 pathways (Mattson, 1997; Minet et al., 2000; Semenza, 1999).