Link Between Pain and Olfaction in an Inherited Sodium Channelopathy

Home , Channelopathy, Ion channel, Nociceptor, Olfactory system, Sodium channel, Taste bud

CLINICAL IMPLICATIONS OF BASIC NEUROSCIENCE RESEARCH

SECTION EDITOR: HASSAN M. FATHALLAH-SHAYKH, MD, PhD Link Between Pain and Olfaction in an Inherited Sodium Channelopathy

Frank Zufall, PhD; Martina Pyrski, PhD; Jan Weiss, PhD; Trese Leinders-Zufall, PhD

n a major breakthrough in our understanding of human olfaction, a recent study showed

that loss-of-function mutations in the voltage-gated sodium channel Nav1.7, encoded by the gene SCN9A, cause a loss of the sense of smell (congenital general anosmia) in mice

and humans. These findings are of special clinical relevance because Nav1.7 was previously Iknown for its essential role in the perception of pain; therefore, this channel is being explored as a promising target in the search for novel analgesics. This advance offers a functional understanding of a monogenic human disorder that is characterized by a loss of 2 major senses—nociception and smell—thus providing an unexpected mechanistic link between these 2 sensory modalities. Arch Neurol. 2012;69(9):1119-1123. Published online June 25, 2012. doi:10.1001/archneurol.2012.21

Studies of mendelian heritable disorders the human nose uses the same molecules and their genotype-phenotype relation- for olfactory signal transduction as the ships have provided major insights into mouse. complex functions of our sensory sys- In the pain system, many of the heri- tems under normal and pathological states. table monogenic pain disorders have been These investigations led to rapid ad- mapped to mutations in genes encoding vances in our understanding of blind- ion channels, leading to a growing list of ness, deafness, and pain disorders. How- channelopathy-associated human pain ever, progress in understanding the genetic syndromes.3-5 One such ion channel that basis of the human sense of smell has been has been the focus of much recent atten- slow. The complete inability to sense odors tion is the voltage-gated and tetrodotoxin- is known as general anosmia; individuals sensitive sodium channel Nav1.7, en- born with this phenotype have congeni- coded by the gene SCN9A (OMIM tal anosmia. With the exception of some 603415).6 Several clinical pain syn- syndromic cases, such as Kallmann syndromes have been linked to different mu- drome, no causative genes for human con- tations in SCN9A. In particular, loss-of- genital general anosmia had been identi- function mutations in SCN9A that cause fied until recently.1 In mice, genetic a congenital inability to experience pain deletion of any of the primary olfactory sig- in humans are of interest.7-10 This syn- nal transduction molecules (Figure 1 and drome, previously known as congenital in- the “Activation of Olfactory Sensory Neu- rons and Odor Perception” section) causes difference to pain (OMIM 24300, autoso- general anosmia.2 However, somewhat mal recessive), has more recently been referred to as channelopathy-associated in- unexpectedly, humans with loss-of- 7 function mutations in these signal trans- sensitivity to pain. Based on several pre- duction genes have not yet been found,1 vious findings, we hypothesized that the and as a result, we do not know whether same Nav1.7 channel that is critical for human pain perception could also be essen- Author Affiliations: Department of Physiology, University of Saarland School of tial for odor perception. In this report, we Medicine, Homburg, Germany. briefly summarize our work and that of

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2 + Cilia CNG Ca -activated Olfactory Mitral cell Axons of mitral cells channel Cl – channel bulb Odor Ca2 + Na + Odor stimulation Knob Glomerulus OR ACIII G Generator potential olf Dendrite 2 + cAMP Ca Cl – ATP Cribriform plate

Soma

Action potentials

Axon Olfactory Cilia OSN Olfactory nerve (cranial nerve I) Glomerulus epithelium Nasal cavity

Figure 1. Schematic drawings of olfactory sensory neuron (OSN) function. A, Electrical activity in canonical mammalian OSNs constitutes a generator potential (a graded membrane depolarization caused by the activity of the primary signal transduction cascade, as shown in part B) and action potentials that propagate along the olfactory axons toward the olfactory bulb. B, Schematic drawing of the primary olfactory signal transduction cascade localized in the OSN cilia. Binding

of an odor molecule to an odor receptor (OR) triggers activation of adenylyl cyclase type 3 (Adcy3 [ACIII in the schematic]) via the heterotrimeric G protein Golf (␣ subunit encoded by Gnal). This process results in the formation of cyclic adenosine monophosphate (cAMP), which in turn activates a calcium ion (Ca2ϩ)–permeable, cyclic nucleotide–gated (CNG) cation channel (primary subunit encoded by Cnga2). Entry of Ca2ϩ through this channel triggers a Ca2ϩ-activated chloride (Cl−) channel, encoded by Ano2. In mice, targeted disruption of Gnal, Adcy3,orCnga2 leads to general anosmia. Disruption of Ano2 is dispensable for olfaction. C, Schematic view showing the anatomical organization of the olfactory system from the OSNs in the olfactory epithelium to the first synapse in the glomeruli of the olfactory bulb. The OSN axons form cranial nerve I. Mitral cell axons form the lateral olfactory tract, which transmits information from the olfactory bulb to cortical areas. Axons from OSNs expressing the same OR terminate in the same glomerulus (indicated by color coding). ATP indicates adenosine triphosphate; Naϩ, sodium ion.

others leading to the identification luminal surface of the nasal cavity, rons (Figure 1C). Twenty-five years of Nav1.7 as a central ion channel for where it ends in a swelling known of intense research have provided de- olfaction of mice and humans. Taken as the dendritic knob (Figure 1A). Ex- tailed information on the mecha- together, these studies identified one tending from each knob are approxi- nisms underlying primary signal of the first causative genes for hu- mately 1 dozen cilia that distribute transduction in mammalian canoni- man congenital general anosmia and within the mucus at the surface of cal OSNs, but, somewhat surpris- provided mechanistic insight into the epithelium. Odor detection starts ingly, the search for genes required the critical role of this channel in when odorants bind to specific re- for action potential generation and axonal and synaptic signaling of ol- ceptor proteins in the olfactory cilia. conduction in these neurons did not factory sensory neurons (OSNs). This initiates a G protein–coupled attract a great deal of attention un- These advances offer a functional second messenger cascade causing til recently. understanding of a monogenic hu- rapid formation of cyclic adeno- man disorder that is characterized by sine monophosphate followed by the HOW THE Nav1.7 CHANNEL a loss of 2 major senses—nocicep- opening of a cyclic adenosine mono- WAS FOUND tion and smell—thus providing an phosphate–gated cation channel unexpected mechanistic link be- (Figure 1B). This primary signal Voltage-gated sodium channels un- tween these 2 sensory modalities. transduction process underlies the derlie the generation and propaga- formation of a graded receptor po- tion of action potentials in electri- ACTIVATION OF OLFACTORY tential that in turn causes the gen- cally excitable cells, such as neurons SENSORY NEURONS AND eration of action potentials. The ac- and muscle cells. These channels ODOR PERCEPTION tion potentials travel along thin form a multigene family consisting unmyelinated OSN axons (which of 9 distinct genes coding for so- The OSNs are the chemoreceptive form the olfactory nerve, also known dium channel ␣ subunits in mice and 6 cells within the sensory epithelium as cranial nerve I) and reach the humans. The Nav1.7 channel (syn- of the nasal cavity (Figure 1). The olfactory bulb, the first relay sta- onyms include neuroendocrine so- initial steps underlying odor per- tion of the olfactory forebrain dium channel [NENa, NE-Na] and pe- ception begin when odor stimuli are (Figure 1C). The OSN axons termi- ripheral nerve type 1 [PN1]) was first detected by these cells, leading to the nate in the olfactory bulb in a de- cloned in 1995 from a human neu- conversion of information con- lineated sphere of neuropil known roendocrine cell line and was ini- tained in odor molecules into elec- as olfactory glomerulus, forming syn- tially called the human neuroendo- trical membrane signals.2 The OSNs apses from the axon terminals on crine sodium channel.11 Subsequently, are bipolar neurons in which the api- juxtaglomerular interneurons and several other groups found the chan- cal dendritic process extends to the mitral/tufted cell projection neu- nel in peripheral nerve cells, includ-

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 ing dorsal root and sympathetic gan- EARLY CASE REPORTS are otherwise essentially normal.” glia, and it was dubbed peripheral ASSOCIATING CONGENITAL Thus, despite the fact that all these nerve type 1.12,13 ANALGESIA AND SENSE investigations pointed, in one way The expression of Nav1.7 in no- OF SMELL DEFICITS or another, to the possibility that the ciceptive neurons sparked an in- sense of smell could be affected in tense interest in its functional role Are all other sensory modalities fully individuals with congenital analge- in the pain system. Because of space preserved in patients with channelo- sia, it remained uncertain whether limitations, we can only highlight pathy-associated insensitivity to this was actually the case. herein a few important steps in this pain? This question remained un- development and refer to several ex- clear until very recently, but a lit- AN ESSENTIAL REQUIREMENT cellent reviews that summarize this erature search uncovered early in- FOR Nav1.7 IN OLFACTION line of research.3-5,14 The first con- dications pointing to an association genital pain syndrome in humans between congenital indifference to In our own work,21 we docu- mapped to SCN9A was published in pain and sense of smell deficits in mented a complete absence of odor 2004,15 indicating an association be- several case reports. Thrush sum- detection in 3 patients with SCN9A tween the Nav1.7 channel and pri- marized the previous literature and loss-of-function mutations and con- mary erythermalgia, a dominant hu- defined congenital insensitivity to cluded that Nav1.7 is an essential re- man disease associated with pain using the criterion that “all quirement for human olfaction. We recurrent episodes of pain. How- other sensory modalities should be proposed that such odor-sensing de- ever, nociceptor-specific deletion of intact or only minimally im- fects are caused by a critical role of 18(p369) Nav1.7 in mice did not produce the paired.” At the same time, he Nav1.7 in the primary OSNs and, same phenotype,16 suggesting that noted that “no convincing evi- consistent with this hypothesis, veri- the role of Nav1.7 in pain was more dence of olfactory sensation was fied that Nav1.7 is normally ex- complex than initially thought. To- found”18(p380) in his patients with con- pressed in human OSNs.21 day, we know that multiple muta- genital insensitivity to pain.18 Losa Subsequently, our experimental tions exist in SCN9A that lead to et al described 3 women with auto- strategy was to move to a mouse strikingly different pain syn- somal recessive congenital analge- model, examine the expression of 3-5,14 dromes. In the context of our sia and complete absence of labor Nav1.7 in the mouse olfactory sys- own work on a potential role of pain; they concluded that “all af- tem, develop a conditional gene de- Nav1.7 in the olfactory system, we fected individuals had anosmia but letion approach, and investigate the became interested at first in a syn- no deficits of autonomic nervous sys- effects of the gene deletion at the cel- drome, now known as channelopa- tem functions.”19(p1303) Hirsch et al lular and systems level. Real-time thy-associated insensitivity to pain, described 2 brothers with congeni- quantitative reverse transcription– which is based on loss-of-function tal indifference to pain and stated in polymerase chain reaction analyses mutations in SCN9A that cause a their abstract that “all other sen- identified Nav1.7 as the most abun- congenital inability to experience sory modes are intact”20(p851) in these dant sodium channel in mouse pain in humans.7 The complete ab- patients. Later in the report, how- OSNs. Remarkably, immunohisto- sence of pain in otherwise seem- ever, they noted that in one of the chemical analysis revealed the most ingly healthy individuals stimu- patients, “neurologic examination striking Nav1.7 staining not in the lated an intense search for analgesics revealed that the patient was anos- olfactory epithelium but in indi- that selectively target this sodium mic, but had normal taste.”20(p852) All vidual glomeruli of the olfactory channel. these reports had in common a lack bulb. Such glomeruli constitute a The finding that mutations in of primary data concerning the smell complex neuropil that includes the SCN9A are responsible for mul- tests. Likewise, no information de- presynaptic OSN boutons (Figure 1). tiple human pain syndromes some- scribed what odors were tested and Colocalization studies verified that what overshadowed other parallel how the results were analyzed, mak- Nav1.7 occupies a critical presynap- developments, suggesting that ing an objective assessment of the tic location at the first synapse in the 21 Nav1.7 could have additional im- stated conclusions difficult. olfactory system, and these re- portant roles in the nervous sys- In a study by Goldberg et al,8 pa- sults were essentially confirmed by 17 22 tem. For instance, Morinville et al tients with confirmed Nav1.7 loss- others. examined the distribution of Nav1.7 of-function mutations underwent We then used the Cre-LoxP sys- in the rat nervous system and con- testing for their ability to sense odors tem to delete the channel in OSNs cluded that the sodium channel is in- and were found, in most cases, to be in a tissue-specific and time- volved in endocrine and auto- anosmic. No actual data of the smell dependent manner. This genetic ap- nomic systems in addition to the tests were provided and no meth- proach revealed offspring that were function of pain systems. They also ods for these tests were described.8 viable but showed a clear deficit in detected the channel in pituitary and Therefore, it remained unclear what suckling behavior,21 which is typi- adrenal glands. Hence, a more de- was tested and how the tests were cal for anosmic mice. tailed analysis of Nav1.7 expression performed. Furthermore, Gold- On the basis of its biophysical 8 in discrete neuronal populations was berg et al stated in the abstract of properties, Nav1.7 has been pro- warranted when we began our work their study that “patients have se- posed to play a more general role in on the role of Nav1.7 in olfaction. verely impaired pain perception, but the transformation of a graded re-

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Nav1.3 deficits. However, in humans with Nav1.7 congenital analgesia, 2 case reports Cav Presynapse Postsynapse pointed out specifically that NS “hewas...anosmic, but taste rec- + / – cNav1.7 ognition was correct though de- layed”18(p373) and “that the patient was anosmic, but had normal taste.”20(p852) NS We believe that these findings are not – / – cNav1.7 yet fully conclusive and will require 50 pA 1 s further investigations. Several other chemosensory systems besides the main olfactory sys- Figure 2. Schematic model (based on original results published by Weiss et al21) depicting the

presynaptic localization of voltage-gated sodium channel Nav1.7 at the first synapse in the olfactory tem exist in the mouse nose. These neural pathway and its critical role in transmitter release. Loss of Nav1.7 function in olfactory sensory systems include an accessory (vom- neurons leads to a loss of postsynaptic currents in mitral cells, indicating a lack of transmitter release at eronasal) olfactory system, a Gru- this synapse. The molecular identity of voltage-gated calcium ion channels (Cav) underlying synaptic release is not yet known. NS indicates nerve stimulation; cNav1.7−/−, conditional homozygous deletion of eneberg ganglion, the organ of Nav1.7; and cNav1.7ϩ/−, conditional heterozygous deletion of Nav1.7. Masera, and the guanylyl cyclase type D system.2 Each of these olfac- ceptor potential into an action po- Nav1.7 in OSNs is essential for the tory subsystems express specific re- tential sequence in sensory neu- display of innate attraction to spe- ceptors, downstream molecules for rons.14 However, we were unable to cies-specific social odors and food second messenger generation, and confirm such a role for Nav1.7 in odors. We also observed that the mu- ion channels for signal detection and OSNs. Instead, we found clear evi- tant mice no longer display several transduction.2 It is currently un- dence that the presence of Nav1.7 in other vital behaviors, including clear whether these subsystems the sections of OSN axons within the predator odor avoidance, short- use the same sodium channels for olfactory glomerulus is an essential term odor learning, and maternal action potential generation and con- and nonredundant requirement for pup retrieval.21 Therefore, our re- duction as canonical OSNs or synaptic transfer at the first syn- sults not only indicated that condi- whether sensory neurons in each apse in the olfactory pathway. In tional deletion of Nav1.7 from OSNs subsystem have evolved distinct OSNs lacking Nav1.7, presynaptic causes a congenital general anos- sets of sodium channels for these electrical stimulation failed to elicit mia phenotype, linking the results functions. postsynaptic responses in olfactory in mice with those in humans, but bulb mitral cells, consistent with a they also provided a mechanistic ba- CONCLUSIONS AND loss of glutamate release in OSNs sis for the observed loss of odor per- FUTURE DIRECTIONS (Figure 2).21 Therefore, we con- ception. Finally, they provided an cluded that Nav1.7 is critical for a unexpected mechanistic link be- The identification of a sodium chan- voltage-dependent influx of cal- tween 2 different sensory modali- nel subunit as a causative gene for cium ions in presynaptic OSN ter- ties, that is, nociception and smell. an inherited form of general anos- minals, although this conclusion has mia has significantly advanced our not yet been shown directly. The A ROLE FOR Nav1.7 IN OTHER understanding of the genetic basis deficit in synaptic signaling was not CHEMOSENSORY SYSTEMS? of the human sense of smell. On the due to a loss of synapse formation basis of these findings, we propose during development.21 Having established an essential role that the first synapse of the olfac- Taken together, these findings re- for Nav1.7 function in olfaction, the tory system should be a rewarding vealed an unexpected function of question arises as to whether this target in the search for additional an- Nav1.7 in the control of presynap- channel also plays a critical role in osmia-related gene defects. Very little tic transmitter release of canonical other chemosensory systems and is still known about the contribu- OSNs (Figure 2). This result is fully whether it might even play a more tion of other voltage-gated chan- consistent with early predictions general role in the control of neu- nels, such as potassium and cal- suggesting that one function of rotransmitter or hormone release. cium channels, to action potential Nav1.7 could be to support the volt- One system that comes to mind is propagation and transmitter re- age-dependent influx of calcium the taste system. Although a func- lease at this synapse. Likewise, many ions, in turn triggering the release tion of sodium channels in taste cells of the molecular components in- of hormones in some neuroendo- is not well established, evidence sug- volved in the presynaptic release ma- crine cells, including adrenal chro- gests that Nav1.7 is expressed in a chinery at this synapse remain to be maffin cells.11 In light of our find- subset of taste cells of the mouse identified. Like the cellular and be- ings, this idea now requires further tongue.23 Because these cells lack ol- havioral phenotypes described in our investigation. factory marker protein expression, work,21 any mutation causing dis- Finally, we analyzed several odor- Cre-mediated Nav1.7 deletion did ruption of synaptic release and sig- guided behaviors in the mutant mice not occur in these cells in our con- naling at the first olfactory synapse and found that the presence of ditional Nav1.7-null mice and, there- will cause massive olfactory dys-

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 function. Loss-of-function muta- Author Contributions: Study con- Loss-of-function mutations in the Nav1.7 gene un- tions in SCN9A are unlikely to be the cept and design: Zufall, Pyrski, Weiss, derlie congenital indifference to pain in multiple human populations. Clin Genet. 2007;71(4): only mutations causing a general an- and Leinders-Zufall. Acquisition of 311-319. osmia phenotype. In this context, a data: Pyrski and Weiss. Analysis and 9. Ahmad S, Dahllund L, Eriksson AB, et al. A stop variety of gain-of-function muta- interpretation of data: Zufall, Pyr- codon mutation in SCN9A causes lack of pain tions for SCN9A have been identi- ski, and Leinders-Zufall. Drafting of sensation. Hum Mol Genet. 2007;16(17):2114- fied.3-5,14 An interesting investiga- the manuscript: Zufall. Critical revi- 2121. tion would be to determine whether sion of the manuscript for important 10. Nilsen KB, Nicholas AK, Woods CG, Mellgren SI, Nebuchennykh M, Aasly J. Two novel SCN9A mu- such gain-of-function mutations al- intellectual content: Zufall, Pyrski, tations causing insensitivity to pain. Pain. 2009; ter odor perception in humans. Weiss, and Leinders-Zufall. Ob- 143(1-2):155-158. With respect to sodium channel tained funding: Zufall and Leinders- 11. Klugbauer N, Lacinova L, Flockerzi V, Hofmann function in OSNs, which channels Zufall. Administrative, technical, and F. Structure and functional expression of a new underlie the conversion of odor- material support: Zufall and Leinders- member of the tetrodotoxin-sensitive voltage- activated sodium channel family from human neu- stimulated graded potentials into ac- Zufall. Study supervision: Zufall and roendocrine cells. EMBO J. 1995;14(6):1084- tion potential sequences remain un- Leinders-Zufall. 1090. clear. We identified Nav1.3 as an Financial Disclosure: None re- 12. Toledo-Aral JJ, Moss BL, He ZJ, et al. Identifica- additional sodium channel ex- ported. tion of PN1, a predominant voltage-dependent so- pressed in OSNs,21 and future gene Funding/Support: This study was dium channel expressed principally in peripheral deletion studies will be required to supported by grants SFB 530 and neurons. Proc Natl Acad Sci U S A. 1997;94 (4):1527-1532. determine its function in olfaction. SFB 894 from the Deutsche Forsch- 13. Sangameswaran L, Fish LM, Koch BD, et al. No human hereditary diseases are ungsgemeinschaft (Drs Zufall and A novel tetrodotoxin-sensitive, voltage-gated so- yet linked to Nav1.3 (SCN3A) dys- Leinders-Zufall) and by the Volks- dium channel expressed in rat and human dorsal function in the Online Mendelian In- wagen Foundation (Dr Leinders- root ganglia. J Biol Chem. 1997;272(23):14805- heritance in Man catalog. Zufall). 14809. 14. Dib-Hajj SD, Cummins TR, Black JA, Waxman SG. At present, researchers are inter- Additional Contributions: We thank From genes to pain: Na v 1.7 and human pain ested in the mechanisms that under- our colleagues who participated in disorders. Trends Neurosci. 2007;30(11):555- lie neural map formation in the mouse the work summarized herein and 563. olfactory system, especially with re- apologize to those whose work we 15. Yang Y, Wang Y, Li S, et al. Mutations in SCN9A, spect to OSN axonal targeting of ol- could not cite owing to space limi- encoding a sodium channel alpha subunit, in pa- factory bulb glomeruli. Some of the tations. Gabriele Moerschbaecher tients with primary erythermalgia. J Med Genet. 2004;41(3):171-174. available evidence indicates that neu- provided administrative help. 16. Nassar MA, Stirling LC, Forlani G, et al. Nociceptor- ral activity plays a role in this pro- specific gene deletion reveals a major role for cess. Future experiments should test REFERENCES Nav1.7 (PN1) in acute and inflammatory pain. 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