Voltage-gated sodium channels and pain-related disorders

Abstract

Voltage-gated sodium channels (VGSCs) are heteromeric transmembrane protein complexes. Nine homologous members, SCN1A-11A, make up the VGSC gene family. Sodium channel isoforms display a wide range of kinetic properties endowing different neuronal types with distinctly varied firing properties. Among the VGSCs isoforms, Nav1.7, Nav1.8 and Nav1.9 are preferentially expressed in the peripheral nervous system. These isoforms are known to be crucial in the conduction of nociceptive stimuli with mutations in these channels thought to be the underlying cause of a variety of heritable pain disorders. This review provides an overview of the current literature concerning the role of VGSCs in the generation of pain and heritable pain disorders.

Human vs. Mouse Nociceptors – Similarities and Differences

“…Different types of voltage-gated sodium channels (VGSCs) play crucial roles in transmitting pain signals to higher brain centers and a variety of pain-related disorders have been linked to mutations in sodium channels ( Liu and Wood, 2011 , Kanellopoulos and Matsuyama, 2016 ). In particular, function-compromising mutations in the genes encoding Na v 1.7, Na v 1.8 and Na v 1.9 are causative to devastating pain disorders.…”

“…As such, functional mutations in Na v 1.7 cause congenital insensitivity to pain (CIP), a disease in which affected individuals can not feel any (physically inflicted) pain while other sensations, such as discrimination of different textures, are apparently not altered. Inherited primary erythromelalgia (IEM), paroxysmal extreme pain disorder (PEPD) and small fiber neuropathies (SFN) are also causally linked to functional mutations of the Na v 1.7 locus ( Kanellopoulos and Matsuyama, 2016 ). Pathological forms of pain can also be caused by mutations in Na v 1.8 and Na v 1.9 channels.…”

“…The involvement of the different channels in pain related diseases in humans, rendered them important targets for the development of new analgesic drugs. However, the distribution of Na v channels in the somatosensory system has not been fully elucidated and thus far drug discovery efforts did not yield any new therapies ( Liu and Wood, 2011 , Han et al, 2016 , Kanellopoulos and Matsuyama, 2016 ). Additionally, discrepancies between Na v -related mouse and human pain phenotypes have been reported ( Nassar et al, 2004 , Weiss et al, 2011 , Minett et al, 2012 , Minett et al, 2014 ).…”

“…Three of the nine homologous members of the VGSC family – Na v 1.7, Na v 1.8 and Na v 1.9 – are important for nociceptive-signal transmission. All three members have also been implicated in heritable pain disorders such as CIP, IEM, PEPD and small fiber neuropathy ( Kanellopoulos and Matsuyama, 2016 ).…”

Role of TrkB-signaling in taste development and function.

“…Interestingly, Nav1.9 is a non-voltage gated sodium channel capable of modulating function of CNS neurons. The most important and best studied role of Nav1.9 is in the function of small unmyelinated sensory neurons that mediate pain (Hoffmann et al, 2017;Kanellopoulos & Matsuyama, 2016). Nav1.9 channels could play a similar role in gustatory neurons as they are also mostly small unmyelinated neurons (Yokota & Bradley, 2016).…”