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Fig. 2. Interaction of calcium in neuroprotection and oxygen-sensing mechanisms in vertebrate 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, (–) indicates an inhibitory one. Oxygen interacts with a variety of target molecules, both at the cell surface, e.g. NMDA receptors (Bickler et al., 2003), K⁺ channels and NADPH oxidase (Prabhakar and Overholt, 2000), and in the cytosol (e.g. HIF-1 and related proteins; Semenza, 1999) in processes that require Ca²⁺ (Mottet et al., 2003). Hypoxia has indirect effects mediated by changes in the bioenergetic state of mitochondria that involve Ca²⁺ (Berridge et al., 2000; Bickler et al., 2000) and reactive oxygen species (ROS) (Haddad and Land, 2000). Signaling via the tyrosine-kinase receptor family also requires Ca²⁺ and results in activation of Akt, an inhibitor of apoptosis (Cheng et al., 2003). Growth factors (Nicole et al., 2001), cytokines and inorganic ions (Millhorn et al., 2000) also may modulate neuronal responses to hypoxia and depend on appropriate [Ca²⁺]_i for their action. Many of these signals converge on calcium-dependent MAP kinase cassettes including the ERK, JNK and p38 pathways (Mattson, 1997; Minet et al., 2000; Semenza, 1999). This figure was modified from Bickler and Donohoe (2002).

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