A sodium channel known for its role in the perception of pain also seems to be necessary for olfaction. The multiple roles of this channel and the diverse effects of its mutations raise intriguing questions. See Article p.186
Generations of scientists were taught that 'the' voltage-gated sodium channel serves as a molecular battery, producing electrical impulses in nerve and muscle cells. However, we now know that mammals, including humans, have nine sodium-channel isoforms (NaV1.1–NaV1.9), encoded by different genes. Of these, NaV1.7 has been the focus of much recent attention, because it is a major contributor to pain perception and so a therapeutic target for pain management1. But, as Weiss et al.2 demonstrate on page 186 of this issue, it is becoming increasingly clear that NaV1.7 also has other neurosensory functions.
NaV1.7 is preferentially expressed in the peripheral nervous system — in dorsal root ganglion (DRG) neurons and sympathetic ganglion neurons3, including the peripheral axonal termini of neurons that perceive pain4. The first insight into the role of this channel in human neurosensory processes came with the discovery that mutations in NaV1.7 cause human pain disorders.
Ion-channel mutations can enhance (gain-of-function) or attenuate (loss-of-function) channel activity. For instance, gain-of-function mutations in NaV1.7, which make it easier to activate this channel and so increase the excitability of pain-signalling DRG neurons, cause inherited erythromelalgia (IEM) — a condition in which, on exposure to mild warmth, patients experience severe burning pain and redness of the skin on the limbs5. Another group of NaV1.7 gain-of-function mutations that interfere with inactivation (transitory silencing of the channel after it has been activated) cause paroxysmal extreme pain disorder (PEPD)6. Patients with PEPD are affected by episodes of pain in the lower body, eyes and jaw.
By contrast, loss-of-function mutations in NaV1.7 — including nonsense, frame-shift and splicing mutations — prevent the production of functional NaV1.7 channels and cause a disorder called channelopathy-associated insensitivity to pain (CIP)7. Patients with CIP do not experience pain even when confronted with extremely painful stimuli: bone fractures, dental extractions and burns cause them no pain.
A hint that NaV1.7 might participate in olfaction came from observations8 that mice lacking NaV1.7 die soon after birth; this was proposed to be due to failure to feed, possibly because the animals could not respond to olfactory cues. Anosmia, or inability to sense smell, has more recently been reported9 in patients with CIP. Weiss et al.2 now show that NaV1.7 plays a crucial, non-redundant part in odour perception. They demonstrate that NaV1.7 is present in axons of human olfactory sensory neurons, and show in mice that it is essential for the initiation of synaptic transmission from olfactory sensory neurons to higher-order neurons that project to the brain.
The finding that NaV1.7 has a pivotal role in olfactory sensory processing presents an interesting parallel to earlier observations that this channel plays a crucial part in pain signalling1. A strategy that is currently being explored for treating pain is specific blockade of the NaV1.7 channel. Whether this approach will be complicated by impaired ability to smell and, if so, whether this will be clinically significant, remain to be determined.
Another question is whether the NaV1.7 gain-of-function mutations that cause IEM and PEPD affect olfactory processing. NaV1.7 mutations responsible for IEM produce hyperexcitability in DRG neurons, which causes pain, but make sympathetic ganglion neurons less excitable, thereby interfering with the regulation of blood flow to the skin10. This complex relationship between genes and their associated traits demonstrates that a single mutation can have very different effects on cellular function when expressed against different cell backgrounds (Fig. 1).
IEM mutations have multidirectional effects because, in addition to enhancing activation, they can depolarize the neuronal membrane10. DRG neurons also contain NaV1.8 sodium channels which, unlike other sodium-channel isoforms, are not inactivated by this level of depolarization11. The depolarization produced by IEM mutations brings DRG neurons closer to the threshold for activation of the NaV1.8 channels, thereby contributing to hyperexcitability of these cells12. By contrast, this depolarization inactivates and effectively silences almost all sodium channels present in sympathetic ganglion neurons — these cells lack NaV1.8 — making it harder for them to fire10. These data hint that the effects of IEM and PEPD mutations on olfactory sensory neurons probably depend on the as yet unknown complement of other ion channels in these cells.
Further complicating the story are compensatory and post-translational changes, which may modulate the effects of mutated ion channels. NaV1.7 is normally present in sympathetic ganglion neurons as well as DRG neurons. Yet, despite the lack of functional NaV1.7 channels in CIP, dysfunction of the autonomic nervous system, which includes sympathetic ganglion neurons, is absent, or relatively subtle, in this disorder7,9. It is not clear whether the relative absence of autonomic dysfunction in CIP is due to the presence of redundant sodium-channel isoforms that can take over the duties of NaV1.7 in sympathetic neurons; to compensatory increases in the expression of other sodium-channel isoforms in these cells; or to increased sensitivity of upstream neurons (denervation hypersensitivity).
Similarly, we do not understand why gain-of-function mutations that enhance the activation of NaV1.7 channels produce pain primarily in the hands and feet (IEM)5, whereas those that affect channel inactivation produce lower-body, eye and jaw pain (PEPD)6. Multiple binding partners, including protein kinases13, modulate NaV1.7, and many other ion channels, but the clinical consequences of this modulation remain unknown.
Taken together, these observations suggest that a combination of factors — including cell-background-dependent and activity-dependent events, epigenetic factors and environmental influences — regulates the activity of normal ion channels, and can modulate the effects of ion-channel mutations even in disorders such as IEM, PEPD and CIP, which are monogenic in the sense that they are produced by a single gene mutation. The full span of these factors and their effects on normal ion channels, as well as the full extent of the ever-expanding range of cellular and clinical abnormalities caused by ion-channel mutations, will undoubtedly become clearer in the next few years.
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