Chronic pain is a pathological state where sensory neurons become hyperexcitable leading to nociceptive neurotransmission in the absence of a painful stimulus. Genetic and functional studies have established the voltage-gated sodium channel Nav1.7 as a major contributor to human pain signaling. Alterations of the trafficking of Nav1.7 appears to be a central mechanism in the etiology of neuropathic pain. Although the dysregulation of Nav1.7 is poorly understood, it is thought to involve mechanisms related to surface trafficking and regulation via protein-protein interactions. Membrane trafficking and functional activity of Nav1.7 is under the control of the axonal collapsin response mediator protein 2 (CRMP2). While CRMP2 can regulate a pleiotropy of functions, regulation of Nav1.7 is specifically guided by small ubiquitin-like modifier (SUMO)ylation. SUMOylation is a dynamic and reversible posttranslational modi?cation of lysine residues in target proteins by SUMOs. CRMP2 SUMOylation relies on its prior phosphorylation by Cdk5. Phosphorylated CRMP2 can also regulate other ion channels such as CaV2.2 but its SUMOylation is exclusive for Nav1.7. In chronic neuropathic pain, increased CRMP2 SUMOylation correlates with enhanced Nav1.7 function. Genetic interference of CRMP2 SUMOylation via expression of a SUMO-null CRMP2 mutant (K374A) in rats with neuropathic pain was sufficient to reverse mechanical allodynia. Similarly, in CRMP2K374A/K374A mice, where CRMP2 SUMOylation is abolished, Nav1.7 currents, trafficking and interaction with CRMP2 were reduced in the dorsal root ganglia (DRG). These mice showed resistance to the development of mechanical allodynia after a neuropathic pain injury. To study in more details the role of CRMP2 SUMOylation in chronic neuropathic pain, I got interested in the sentrin/SUMO- specific protease (SENPs) that catalyze the deSUMOylation of proteins. Interestingly, increasing deSUMOylation with overexpression of sentrin/SUMO-specific protease SENP1 and/or SENP2 CRMP2-expressing heterologous cells decreases surface Nav1.7 expression and currents. Although SUMO-1 and SENP1 are expressed in the spinal cord and in DRG neurons their roles in Nav1.7 function and pain as never been investigated. Most of the past work focused on studying the effects of CRMP2 SUMOylation; there is only limited evidence regarding the study of this modification in reverse. Therefore, our overall hypothesis is that by enhancing CRMP2 deSUMOylation by SENP1 can, in turn, control Nav1.7-dependent DRG neuron excitability and contribute to initiation and maintenance of chronic neuropathic pain.
SUMOylation is a highly regulated process that is counteracted by specialized enzymes known as small ubiquitin-related modifier (SUMO) proteases. The recent discovery that SUMOylation of a cellular protein (CRMP2) can contribute to the activity of a key sodium channel (Nav1.7) involved in pain means that removal of SUMO by proteases may also contribute to the pathophysiology of neuropathic pain. This study will improve our understanding of the mechanisms underlying Nav1.7 in human pain and may aid in the design of new therapeutic approaches.
