Nitric Oxide-Mediated Posttranslational Modifications: Impacts at the Synapse

Figure 2

Simplified pathways of synaptic transmission and effects of nitrergic posttranslational modifications. (a) Left, presynapse; right, postsynapse: showing signalling steps involved in transmitter release and neurotransmitter receptor function. Ca²⁺-dependent activation of postsynaptic nNOS leads to nitrergic modifications of molecules (colour-coded) which are involved in synaptic transmission in pre- and postsynaptic compartments. NO diffuses within the postsynaptic cell but also into the presynapse. Presynaptic assembly of the prefusion SNARE complex (such as the vesicular v-SNARE complex protein synaptobrevin assemblies with the plasma membrane SNARE proteins syntaxin and SNAP-25) and membrane proteins in close proximity to the active zone (AZ) results in a prefusion state of the vesicle. In a further step, Munc-18 associates with syntaxin-1 when syntaxin-1 is in a closed conformation; as syntaxin-1 opens during SNARE complex assembly it enables subsequent vesicle fusion and transmitter release following Ca²⁺ influx. Ca²⁺ release from intracellular stores via ryanodine receptors (RyR1) as well as influx through voltage-gated Ca²⁺ channels (VGCC, in grey) in response to incoming action potentials (AP) leads to the accumulation of intracellular Ca²⁺ levels and promoting of vesicle fusion. After fusion pore opening, the resulting SNARE complexes are disassembled and vesicles are recycled (dynamin-mediated), refilled with neurotransmitter, and reused for release. Postsynaptic receptors, excitatory NMDAR, and inhibitory GABAR are S-nitrosylated. Furthermore, the scaffolding proteins PSD-95, Stargazin, NSF, and Gephyrin are also nitrosylated with various functional outcomes. Ultimately, these modifications in addition to the canonical sGC/cGMP pathway (in grey) will alter the synaptic response and change AP firing characteristics following nitrergic signalling. (b) All colour-coded proteins have been shown to be subject to nitrergic posttranslational modifications with their specific residues indicated.

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