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

concentration of NO (Hess et al., 1993; Renteria and Constantine-Paton, 1996; Ernst et al., 2000;
He et al., 2002; Trimm and Rehder, 2004). Recently, S-nitrosylation of microtubule-associated
protein 1B (MAP1B) has been suggested to mediate NO-induced axon retraction in cultured
vertebrate neurons (Stroissnigg et al., 2007). In Helisoma buccal ganglion, NO regulates growth
cone filopodial behavior via sGC, PKG and cyclic adenosine diphosphate ribose (cADPR), which
causes the release of calcium from intracellular stores via the ryanodine receptor (RyRs)
(Welshhans and Rehder, 2005). The downstream effector proteins for NO/cGMP signaling, PKG
(Yue et al., 2008) and CNGs (Togashi et al., 2008) have been shown to mediate ephrin-A5-induced
growth cone collapse and Sema3A-induced growth cone repulsion, respectively. Furthermore, the
NO/cGMP signaling has been shown to negatively regulate the Ca 2+ -induced Ca 2+ release (CICR)
through RyRs to control directional polarity of DRG axon guidance (Tojima et al., 2009). Here, a
Ca 2+ signal produced by photolysing caged Ca 2+ caused growth cone repulsion on laminin substrate
which was converted into attraction by pharmacological blocking of NO/cGMP pathway or genetic
deletion of nNOS.
On the other hand, studies performed in vitro on PC12 cells (Hindley et al., 1997; Rialas et al, 2000;
Yamazaki et al., 2001) and neuroblastoma cells (Evangelopoulos et al., 2010) indicated that NO
increases neurite outgrowth. In developing antenna of the grasshopper embryo where two siblings
of pioneer neurons establish the first two axonal pathways to the CNS, NO/cGMP signaling has
been shown to mediate axonogenesis (Seidel and Bicker, 2000). Here, pharmacological inhibition
of NOS and sGC resulted in abnormal pattern of pathfinding, loss of axon emergence and axon
retraction suggesting that NO/cGMP signaling is a positive regulator of neurite elongation. Recent
study indicated that S-nitrosylation HDAC2 caused by neurotrophin induced NO signaling is
necessary for dendritic outgrowth of embryonic cortical neurons (Nott et al., 2008). In models of
CNS injury, the regeneration of axons in embryonic insect (Stern and Bicker, 2008) and optic nerve
in the goldfish (Koriyama et al., 2009) was facilitated by NO/cGMP signaling pathway.
1.2.4. Synaptogenesis
Synaptogenesis can be defined as the assembly of pre- and postsynaptic proteins into the highly
specific structure of the synapse. These major components of glutamatergic synapses includes;
synaptic vesicles (SVs), glutamate receptors, active zone proteins, postsynaptic density (PSD)
scaffolding proteins, and trans-synaptic adhesion molecules. The pre-and postsynaptic components
of a synapse must accumulate at sites of physical contact between axons and dendrites with precise
timing (McAllister, 2007). During development, synaptogenesis is tightly coupled to neuronal
differentiation and formation of neuronal circuitry. For example, shortly after neurons differentiate
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