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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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