SNO-ing at the Nociceptive Synapse?

Nitric oxide is generally considered a pronociceptive retrograde transmitter that, by activation of soluble guanylyl cyclase-mediated cGMP production and activation of cGMP-dependent protein kinase, drives nociceptive hypersensitivity. The duality of its functions, however, is increasingly recognized. This review summarizes nitric-oxide-mediated direct S-nitrosylation of target proteins that may modify nociceptive signaling, including glutamate receptors and G-protein-coupled receptors, transient receptor potential channels, voltage-gated channels, proinflammatory enzymes, transcription factors, and redoxins. S-Nitrosylation events require close proximity of nitric oxide production and target proteins and a permissive redox state in the vicinity. Despite the diversity of potential targets and effects, three major schemes arise that may affect nociceptive signaling: 1) S-Nitrosylation-mediated changes of ion channel gating properties, 2) modulation of membrane fusion and fission, and thereby receptor and channel membrane insertion, and 3) modulation of ubiquitination, and thereby protein degradation or transcriptional activity. In addition, S-Nitrosylation may alter the production of nitric oxide itself.