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Link Between Pain and Olfaction in an Inherited Sodium Channelopathy

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Link Between Pain and Olfaction in an Inherited Sodium Channelopathy 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 understand- ing 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 syn- dromes 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 hu- man 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 ARCH NEUROL / VOL 69 (NO. 9), SEP 2012 WWW.ARCHNEUROL.COM 1119 ©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 A B C 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- ARCH NEUROL / VOL 69 (NO. 9), SEP 2012 WWW.ARCHNEUROL.COM 1120 ©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
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