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Nitric Oxide Mediated Signal Transduction in Networks of Human ...

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concentration <strong>of</strong> NO (Hess et al., 1993; Renteria and Constant<strong>in</strong>e-Paton, 1996; Ernst et al., 2000;<br />

He et al., 2002; Trimm and Rehder, 2004). Recently, S-nitrosylation <strong>of</strong> microtubule-associated<br />

prote<strong>in</strong> 1B (MAP1B) has been suggested to mediate NO-<strong>in</strong>duced axon retraction <strong>in</strong> cultured<br />

vertebrate neurons (Stroissnigg et al., 2007). In Helisoma buccal ganglion, NO regulates growth<br />

cone filopodial behavior via sGC, PKG and cyclic adenos<strong>in</strong>e diphosphate ribose (cADPR), which<br />

causes the release <strong>of</strong> calcium from <strong>in</strong>tracellular stores via the ryanod<strong>in</strong>e receptor (RyRs)<br />

(Welshhans and Rehder, 2005). The downstream effector prote<strong>in</strong>s for NO/cGMP signal<strong>in</strong>g, PKG<br />

(Yue et al., 2008) and CNGs (Togashi et al., 2008) have been shown to mediate ephr<strong>in</strong>-A5-<strong>in</strong>duced<br />

growth cone collapse and Sema3A-<strong>in</strong>duced growth cone repulsion, respectively. Furthermore, the<br />

NO/cGMP signal<strong>in</strong>g has been shown to negatively regulate the Ca 2+ -<strong>in</strong>duced Ca 2+ release (CICR)<br />

through RyRs to control directional polarity <strong>of</strong> DRG axon guidance (Tojima et al., 2009). Here, a<br />

Ca 2+ signal produced by photolys<strong>in</strong>g caged Ca 2+ caused growth cone repulsion on lam<strong>in</strong><strong>in</strong> substrate<br />

which was converted <strong>in</strong>to attraction by pharmacological block<strong>in</strong>g <strong>of</strong> NO/cGMP pathway or genetic<br />

deletion <strong>of</strong> nNOS.<br />

On the other hand, studies performed <strong>in</strong> vitro on PC12 cells (H<strong>in</strong>dley et al., 1997; Rialas et al, 2000;<br />

Yamazaki et al., 2001) and neuroblastoma cells (Evangelopoulos et al., 2010) <strong>in</strong>dicated that NO<br />

<strong>in</strong>creases neurite outgrowth. In develop<strong>in</strong>g antenna <strong>of</strong> the grasshopper embryo where two sibl<strong>in</strong>gs<br />

<strong>of</strong> pioneer neurons establish the first two axonal pathways to the CNS, NO/cGMP signal<strong>in</strong>g has<br />

been shown to mediate axonogenesis (Seidel and Bicker, 2000). Here, pharmacological <strong>in</strong>hibition<br />

<strong>of</strong> NOS and sGC resulted <strong>in</strong> abnormal pattern <strong>of</strong> pathf<strong>in</strong>d<strong>in</strong>g, loss <strong>of</strong> axon emergence and axon<br />

retraction suggest<strong>in</strong>g that NO/cGMP signal<strong>in</strong>g is a positive regulator <strong>of</strong> neurite elongation. Recent<br />

study <strong>in</strong>dicated that S-nitrosylation HDAC2 caused by neurotroph<strong>in</strong> <strong>in</strong>duced NO signal<strong>in</strong>g is<br />

necessary for dendritic outgrowth <strong>of</strong> embryonic cortical neurons (Nott et al., 2008). In models <strong>of</strong><br />

CNS <strong>in</strong>jury, the regeneration <strong>of</strong> axons <strong>in</strong> embryonic <strong>in</strong>sect (Stern and Bicker, 2008) and optic nerve<br />

<strong>in</strong> the goldfish (Koriyama et al., 2009) was facilitated by NO/cGMP signal<strong>in</strong>g pathway.<br />

1.2.4. Synaptogenesis<br />

Synaptogenesis can be def<strong>in</strong>ed as the assembly <strong>of</strong> pre- and postsynaptic prote<strong>in</strong>s <strong>in</strong>to the highly<br />

specific structure <strong>of</strong> the synapse. These major components <strong>of</strong> glutamatergic synapses <strong>in</strong>cludes;<br />

synaptic vesicles (SVs), glutamate receptors, active zone prote<strong>in</strong>s, postsynaptic density (PSD)<br />

scaffold<strong>in</strong>g prote<strong>in</strong>s, and trans-synaptic adhesion molecules. The pre-and postsynaptic components<br />

<strong>of</strong> a synapse must accumulate at sites <strong>of</strong> physical contact between axons and dendrites with precise<br />

tim<strong>in</strong>g (McAllister, 2007). Dur<strong>in</strong>g development, synaptogenesis is tightly coupled to neuronal<br />

differentiation and formation <strong>of</strong> neuronal circuitry. For example, shortly after neurons differentiate<br />

6

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