spins in each cloud are then more likely to col-lide, reverse their velocity and travel freely backward, because in the backward direction all atoms are in the same spin state and are pre-vented from colliding by the Pauli exclusion principle.

After the bouncing subsided, the behav-iour of the clouds was much like that of two masses connected by an oil dashpot that heav-ily damps their relative motion. The measured damping exhibited a maximum at a certain temperature and decreased as the temperature

was further reduced, suggesting that the colli-sion rate was suppressed at low temperature, as expected for a Fermi liquid, and that the resistance to spin flow decreased. From these measurements, Sommer et al.2 conclude that, for spin currents, pair formation cannot pro-duce bosons to enhance the collision rate: spin-up and spin-down atoms must move in opposite directions to produce a net spin current, and so pair formation cannot occur as it does for mass flow. Thus, developing a detailed understanding of transport in Fermi

gases presents further challenges for the theory of strongly correlated many-body systems. ■

John E. Thomas is in the Department of Physics, Duke University, Durham, North Carolina 27708, USA. e-mail: jet@phy.duke.edu

1. Thomas, J. E. Phys. Today 63(5), 34–37 (2010).2. Sommer, A., Ku, M., Roati, G. & Zwierlein, M. W.

Nature 472, 201–204 (2011).3. Cao, C. et al. Science 331, 58–61 (2011).4. Bruun, G. M. & Smith, H. Phys. Rev. A 75, 043612

(2007).

N E U R O S C I E N C E

Channelopathies have many facesA 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

S T E P H E N G . W A X M A N

Generations of scientists were taught that ‘the’ voltage-gated sodium channel serves as a molecular battery, produc-

ing 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 differ-ent 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 thera-peutic 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 excit-ability of pain-signalling DRG neurons, cause inherited erythromelalgia (IEM) — a condi-tion 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 con-fronted 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, possi-bly 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 trans-mission from olfactory sensory neurons to

a Pain pathways b Autonomic pathways c Olfactory pathways

Gain-of-function(enhanced activation)

Gain-of-function(impaired

inactivation)

Loss-of-function

DRG neuron,hyperexcitability

IEM:pain in

hands and feet

Sympathetic ganglionneuron, lessexcitable

DRG neuron,hyperexcitability

IEM:cutaneous

vasomotor abnormality ?

?

?

?

?

?

PEPD:pain in lower

body, eyes, jaw

PEPD:skin �ushing,

watering of eyes/mouth

CIP:inability

to feel painNo reported

autonomic dysfunction

Olfactory sensoryneuron, impairedsignalling

Anosmia

DRG neuron,presumably lessexcitable

Figure 1 | Multiple effects of mutations in the NaV1.7 ion channel. a, Gain-of-function mutations in NaV1.7 increase the excitability of dorsal root ganglion (DRG) neurons, thereby producing pain in inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). Loss-of-function mutations of this channel decrease excitability in DRG neurons, and produce channelopathy-associated insensitivity to pain (CIP). b, Gain-of-function mutations of NaV1.7 reduce the excitability of sympathetic ganglion neurons in IEM, thereby interfering with vasomotor (blood-vessel calibre) control in the skin. They may also perturb the firing of sympathetic ganglion neurons in PEPD, in which skin flushing, watering of the eyes and mouth, and slowed heart rate accompany pain attacks. c, Weiss et al.2 show that, in the olfactory system, loss-of-function mutations in NaV1.7 interfere with signalling from olfactory sensory neurons to upstream nerve cells, causing anosmia, the inability to smell.

1 4 A P R I L 2 0 1 1 | V O L 4 7 2 | N A T U R E | 1 7 3

NEWS & VIEWS RESEARCH

© 2011 Macmillan Publishers Limited. All rights reserved

higher-order neurons that project to the brain.The finding that NaV1.7 has a pivotal role in

olfactory sensory processing presents an inter-esting 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 com-plicated 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 hyper-excitability in DRG neurons, which causes pain, but make sympathetic ganglion neu-rons 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 hyperexcit-ability of these cells12. By contrast, this depo-larization inactivates and effectively silences almost all sodium channels present in sym-pathetic 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 com-plement of other ion channels in these cells.

Further complicating the story are compen-satory and post-translational changes, which may modulate the effects of mutated ion chan-nels. 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 nerv-ous system, which includes sympathetic gan-glion 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 activa-tion 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 chan-nels, 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 mod-ulate 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. ■

Stephen G. Waxman is in the Department of Neurology and the Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, USA. He is also at the Veterans Affairs Connecticut Healthcare System, West Haven. e-mail: stephen.waxman@yale.edu

1. Waxman, S. G. Nature 444, 831–832 (2006).2. Weiss, J. et al. Nature 472, 186–190 (2011).3. Toledo-Aral, J. J. et al. Proc. Natl Acad. Sci. USA 94,

1527–1532 (1997).4. Persson, A.-K. et al. Mol. Pain 6, 84 (2010).5. Dib-Hajj, S. D. et al. Brain 128, 1847–1854 (2005).6. Fertleman, C. R. et al. Neuron 52, 767–774 (2006). 7. Cox, J. J. et al. Nature 444, 894–898 (2006).8. Nassar, M. A. et al. Proc. Natl Acad. Sci. USA 101,

12706–12711 (2004).9. Goldberg, Y. P. et al. Clin. Genet. 71, 311–319 (2007).10. Rush, A. M. et al. Proc. Natl Acad. Sci. USA 103,

8245–8250 (2006).11. Akopian, A. N., Sivilotti, L. & Wood, J. N. Nature 379,

257–262 (1996). 12. Harty, T. P. et al. J. Neurosci. 26, 12566–12575 (2006).13. Stamboulian, S. et al. J. Neurosci. 30, 1637–1647

(2010).

M A M M A L I A N E V O L U T I O N

A jaw-dropping earA fossil from the Early Cretaceous provides insight into the evolution of the hearing apparatus in mammals. Anchoring the eardrum was, it seems, an essential step in freeing the middle ear from the jaw. See Article p.181

A N N E W E I L

The 120-million-year-old lake sediments of the Jiufotang Formation of Liaoning, China, have yielded another scientific

bounty: the near-complete skeleton of a fossil mammal, Liaoconodon. This fossil, described by Meng et al. (page 181 of this issue)1, is nota-ble in illuminating a key phase in the evolution of the mammalian ear.

The exceptional preservation of fossils in the Jiufotang Formation, which has offered up entire fish, pterosaurs and feathered dinosaurs, is no longer a surprise. But the cornucopia of knowledge provided by such detail seems end-less. When the new specimen’s small, flattened but complete skull was prepared, the palae-ontologists found that the tiny bones of the middle ear were still in place, and still attached to the lower jaw1. In all extant mammals, they are separated from it. Their attachment in Liaoconodon might support the contention that the ear bones remained tenuously attached to the jaw higher in the evolutionary tree of mammals than some have supposed2.

The middle ears of living mammals contain three small bones, the malleus, incus and stapes, which conduct vibrations from the eardrum to the inner ear. The eardrum itself stretches across a fourth small bone, the ecto-tympanic. The malleus and ectotympanic have long been understood to have been primitively

part of the lower jaw, or mandible; the joint between the malleus and incus is homologous to the jaw joint in reptiles. How, when and how many times these ossicles detached from the mandible during the course of mammalian evolution is a topic of some controversy2.

Liaoconodon is a member of a lineage of mammals, the eutriconodonts, that is well-documented and diverse in the Liaoning beds, but has no living representatives. Eutri-conodonts are unusual among vertebrates in having had an ossified Meckel’s cartilage3,4. In extant mammals, Meckel’s cartilage is a rod that condenses early in an individual’s devel-opment and is later sheathed in dermal bone that will become the lower jaw. The cartilage itself is resorbed, leaving only its posterior end, which ossifies and becomes the posterior part of the malleus. In eutriconodonts, instead of degenerating, Meckel’s cartilage separated from the part of the malleus it formed and then turned to bone, persisting in adult individu-als. It is this element that the ear ossicles are contacting.

The exquisite preservation of Liaoconodon allowed Meng et al.1 to identify the suture between the anterior and posterior parts of the malleus; it is the anterior process, derived not from cartilage but from a dermal bone of the jaw, that broadly contacts the ossified Meckel’s cartilage and wraps part-way around it. The ectotympanic mostly contacts the

1 7 4 | N A T U R E | V O L 4 7 2 | 1 4 A P R I L 2 0 1 1

NEWS & VIEWSRESEARCH

© 2011 Macmillan Publishers Limited. All rights reserved