Post-translational modifications of voltage-gated sodium channels in chronic pain syndromes

作者：Laedermann Cedric J^*; Abriel Hugues; Decosterd Isabelle

来源：Frontiers in Pharmacology, 2015, 6: 263.

DOI：10.3389/fphar.2015.00263

• voltage-gated sodium channels
• post-translational modification
• chronic pain
• hyperexcitability
• nociceptive neurons

In the peripheral sensory nervous system the neuronal expression of voltage-gated sodium channels (Nays) is very important for the transmission of nociceptive information since they give rise to the upstroke of the action potential (AP). Na(V)s are composed of nine different isoforms with distinct biophysical properties. Studying the mutations associated with the increase or absence of pain sensitivity in humans, as well as other expression studies, have highlighted Na(V)1.7, Na(V)1.8, and Na(V)1.9 as being the most important contributors to the control of nociceptive neuronal electrogenesis. Modulating their expression and/or function can impact the shape of the AP and consequently modify nociceptive transmission, a process that is observed in persistent pain conditions. Post-translational modification (PTM) of Nays is a well-known process that modifies their expression and function. In chronic pain syndromes, the release of inflammatory molecules into the direct environment of dorsal root ganglia (DRG) sensory neurons leads to an abnormal activation of enzymes that induce Na(V)s PTM. The addition of small molecules, i.e., peptides, phosphoryl groups, ubiquitin moieties and/or carbohydrates, can modify the function of Na(V)s in two different ways: via direct physical interference with Na-V gating, or via the control of Na-V trafficking. Both mechanisms have a profound impact on neuronal excitability. In this review we will discuss the role of Protein Kinase A, B, and C, Mitogen Activated Protein Kinases and Ca++/Calmodulin-dependent Kinase II in peripheral chronic pain syndromes. We will also discuss more recent findings that the ubiquitination of Na(V)1.7 by Nedd4-2 and the effect of methylglyoxal on Na(V)1.8 are also implicated in the development of experimental neuropathic pain. We will address the potential roles of other PTMs in chronic pain and highlight the need for further investigation of PTMs of Nays in order to develop new pharmacological tools to alleviate pain.

• 出版日期2015-11-5