Function and regulation of sodium channel NaV1.7 in pain

Function and regulation of sodium channel NaV1.7 in pain (Dr. Jing Zhao, Nociception Lab, WIBR, UCL)

Pain is a major clinical problem and many types of chronic pain are difficult to treat. Both human and mouse genetic studies show that the voltage-gated sodium channel Na_V1.7 plays a critical role in pain pathways. As patients with recessive loss of function Na_V1.7 mutations are normal (apart from being pain-free and anosmic) this channel may be an excellent analgesic drug target. As a large membrane protein, however, its function and regulation in pain mechanisms is not completely understood. To investigate the channel-interacting proteins of Na_V1.7 we generated an epitope-tagged Na_V1.7 mouse line. Here, I will demonstrate that many interacting protein partners including known and novel ones, such as membrane-trafficking protein synaptotagmin-2 (Syt2) and G protein-regulated inducer of neurite outgrowth (Gprin1), have been identified with affinity-purification and mass spectrometry in these mice. We also examined the distribution of Na_V1.7 in the spinal cord of these mice using immunohistochemistry and immune-EM. Our data show that Na_V1.7 is not only expressed in pre-synaptic terminals of DRG neurons but, unexpectedly, also in the post-synaptic terminals of spinal cord. Furthermore, our electrophysiological data indicate that Na_V1.7 plays a key role in regulating intrinsic firing properties in a subset of dorsal horn interneurons of the spinal cord. To summarise, our data demonstrate that Na_V1.7 plays an important role not only in conduction of pain signals in peripheral sensory neurons, but also in signal transmission in the spinal dorsal horn. These results provide new mechanistic insights into the function of Na_V1.7.