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Too fast – Rare neuropathic pain state associated with easy activation of NaV1.9
Susanna B Park1 and Mark D Baker2
1. Brain and Mind Centre, Sydney Medical School, University of Sydney, Australia
2. Blizard Institute, Queen Mary University of London, 4 Newark Street, London E1 2AT
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
pain disorders. 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 ultra-slow activation that was not eliminated by Nav1.8 knock-out (e.g. [1]),
although the gene functionality in neurons was not proven until Nav1.9 was painstakingly
heterologously expressed in murine Nav1.9 knock-out neurons (e.g. [2]). Almost ten 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 ultra-slow activation kinetics and prominent persistent current characteristic of Nav1.9
contribute to resting membrane potential and modulation of excitability in response to
depolarization [3]. Nav1.9 plays a prominent role in inflammatory pain by depolarizing the
membrane to firing threshold [3] and is extraordinarily sensitive to G-protein pathway
modulation (e.g. [4]). Given this biophysical profile and expression pattern in nociceptors, it
is not surprising that aberrant Nav1.9 activation or up-regulation is associated with increased
excitability and pain.
In the present issue of JNNP, Han et al on p XX 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. Consistent with the latter, evidence
for the functional importance of NaV1.9 in pain signalling in the gut has recently been
uncovered (5). Electrophysiological recordings from neurons with mutant channels
demonstrated a hyperpolarizing shift in channel activation, acceleration of activation and
depolarization 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, but also shed light
on the normal functioning of the channel and provide 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, 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 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 further strengthen the role of Nav1.9 as a valid target in
human pain disorders and suggest that there is more to uncover regarding the translation of
Na+ channel kinetic properties to specific clinical phenotypes.
References
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