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The spectrum of sodium (Na+) channel-associated pain disorders is expanding, with mutations in the Na+ channel isoforms Nav1.7, Nav1.8 and Nav1.9 all associated with human syndromes.1 ,2 However, the characterisation of clinical and electrophysiological properties of mutations in Nav1.9 has trailed behind those of Nav1.7 and Nav1.8. Identification of the functional role of Nav1.9 in sensory neurons followed the documentation of a persistent Na+ current with ultraslow activation that was not eliminated by Nav1.8 knockout,3 although the gene functionality in neurons was not proven until Nav1.9 was painstakingly heterologously expressed in murine Nav1.9 knockout neurons.4 Almost 10 years later the heterologous expression of wild type and mutant human channels appears routine and has yielded important insights into the behaviour of Na+ channels.
The ultraslow activation kinetics and prominent persistent current characteristic of Nav1.9 contribute to resting membrane potential and modulation of excitability in response to depolarisation.5 Nav1.9 plays a prominent role in inflammatory pain by depolarising the membrane to firing threshold5 and is extraordinarily sensitive to G-protein pathway modulation.6 Given this biophysical profile and expression pattern in nociceptors, it is not surprising that aberrant Nav1.9 activation or upregulation is associated with increased excitability and pain.
In the present issue of JNNP, Han et al7 detail a novel mutation in the voltage sensor of Nav1.9 (p.Arg222His) associated with an inherited episodic pain disorder characterised by pain in the extremities and gastrointestinal disturbance. Electrophysiological recordings from neurons with mutant channels demonstrated a hyperpolarising shift in channel activation, acceleration of activation and depolarisation of the resting potential. Multistate modelling predicted that the mutation would facilitate the opening of the channel by destabilising the closed state of the channel. Taken in total, the faster channel gating gives rise to a state of hyperexcitability which cannot be accommodated by the normal adaptive mechanisms present in neuronal membrane.
Han et al provide a molecular mechanism for this neuropathic pain state, and also shed light on the normal functioning of the channel, providing us with an insight into why the extraordinarily slow channel activation kinetics of Nav1.9 have arisen and have been maintained across generations. While these mechanistic studies reveal the biophysical basis for pain, there is still much to uncover about the clinical manifestations and phenotype. The clinical phenotype of pain and gastrointestinal disturbance matches the expression pattern of Nav1.9 in small cutaneous and visceral afferents and evidence for the functional importance of Nav1.9 in pain signalling in the gut has recently been uncovered.8
However, the link between channel properties and clinical symptoms is not absolute. There is no clear mechanistic basis for the improvement of symptoms with age, and conversely deterioration with age has been described with other sodium channelopathies. Detailed clinical phenotyping and longitudinal assessment will be required to fully understand the impact of different Nav1.9 mutations at a phenotypic level. The present results suggest that there is more to uncover regarding the translation of Na+ channel kinetic properties to specific clinical phenotypes. In addition, these findings further strengthen the role of Nav1.9 as a valid target in human pain disorders. While the inherited neuropathic pain disorder detailed by Han et al is rare, the identification of further links between Na+ channel phenotypes and pain will lead to greater understanding of the mechanisms of pain more generally and assist in the development of novel, targeted treatments for pain.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
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