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Sodium Channels and Mammalian Sensory Raouf et al. Molecular Pain 2012, 8:21 http://www.molecularpain.com/content/8/1/21 MOLECULAR PAIN RESEARCH Open Access Sodium channels and mammalian sensory mechanotransduction Ramin Raouf1,2*†, Francois Rugiero1†, Hannes Kiesewetter1, Rachel Hatch1, Edith Hummler5, Mohammed A Nassar1,4, Fan Wang6 and John N Wood1,3* Abstract Background: Members of the degenerin/epithelial (DEG/ENaC) sodium channel family are mechanosensors in C elegans, and Nav1.7 and Nav1.8 voltage-gated sodium channel knockout mice have major deficits in mechanosensation. b and gENaC sodium channel subunits are present with acid sensing ion channels (ASICs) in mammalian sensory neurons of the dorsal root ganglia (DRG). The extent to which epithelial or voltage-gated sodium channels are involved in transduction of mechanical stimuli is unclear. Results: Here we show that deleting b and gENaC sodium channels in sensory neurons does not result in mechanosensory behavioural deficits. We had shown previously that Nav1.7/Nav1.8 double knockout mice have major deficits in behavioural responses to noxious mechanical pressure. However, all classes of mechanically activated currents in DRG neurons are unaffected by deletion of the two sodium channels. In contrast, the ability of Nav1.7/Nav1.8 knockout DRG neurons to generate action potentials is compromised with 50% of the small diameter sensory neurons unable to respond to electrical stimulation in vitro. Conclusion: Behavioural deficits in Nav1.7/Nav1.8 knockout mice reflects a failure of action potential propagation in a mechanosensitive set of sensory neurons rather than a loss of primary transduction currents. DEG/ENaC sodium channels are not mechanosensors in mouse sensory neurons. Keywords: Mechanotransduction, Sodium channels, Pain, Nav1.7, Nav1.8, ENaCs Background Some invertebrate sodium channels of the ENaC/DEG The identity of the noxious mechanotransduction chan- superfamily are mechanosensors [4-6] but it is still nels in sensory neurons remains elusive but increasing unknown if any mammalian epithelial or voltage gated evidence, particularly from knockout mice, indicates sodium channels participate in noxious mechanotrans- that transduction of noxious stimuli are carried out by duction. Evidence from knockout mice suggests that more than one channel [1]. Many candidates have been ASICs are not involved in sensory transduction [7]. proposed, however none has fulfilled the requirements Epithelial Na+ channels (ENaC) are voltage-independent, of a bona fide noxious mechanotransducer that is Na+-selective ion channels composed of a, b and g sub- expressed in mechanosensitive neurons, is activated by units; the a subunit is necessary for channel function high threshold mechanical stimulation, and can be [8]. ENaC channels can be activated by membrane modulated by inflammatory mediators [2]. The list of stretch and shear stress [9-11]. In mammals, the potential mechanotransducers include TRP channels, mechanosensitive hair cells of the cochlea express potassium channels (see [1] for review), and the novel ENaCs, but genetic deletion of aENaC does not perturb channel family Fam38a and b (Piezo1 and 2) transmem- mechanotransduction in these cells [12]. brane proteins [3] Studies in DRG neurons show the presence of b-and g subunits in both rat and mouse but report contradic- * Correspondence: [email protected]; [email protected] tory data about the presence of the a channels in these † Contributed equally neurons. However, functional ASIC channels with which 1Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK ENaC subunits can heteromultimerise are broadly Full list of author information is available at the end of the article © 2012 Raouf et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Raouf et al. Molecular Pain 2012, 8:21 Page 2 of 12 http://www.molecularpain.com/content/8/1/21 expressed in DRG neurons [13]. b and gENaCs were The possible involvement of b and g ENaC channels in found in sensory nerve terminals associated with Merkel low threshold mechanosensation (light touch) was studied cells, Meissner and small lamellated corpuscles in the using Advillin-Cre/bENaC flox/flox and Advillin-Cre/gENaC skin [14] whilst all three ENaC subunits were detected flox/flox mice, in which b or g ENaC subunits are deleted in in rat trigeminal sensory nerves [15], in rat mechanosen- all DRG neurons. These mice allow us to assess the possi- sitive nerve afferents innervating the muscle spindles ble role of these channels in large DRG neurons responsi- where they contribute to mechanotransduction [16]. ble for low threshold mechanotransduction. Pan-DRG The extent to which these sodium channels participate knockout of ENaC b-andg subunits did not lead to any in mammalian sensory mechanotransduction remains change in light touch sensation as measured in the Von unclear. Frey test (Figure 1b, f). These results combined with the Voltage-gated sodium channels underpin the propaga- Randall-Selitto data show that b-andg subunits do not tion of action potentials. However, whether they also have a mechanotransducing function in DRG neurons. contribute to mechanotransduction is not known. A Thermosensation was also tested in Advillin-Cre/ number of Nav1.7 mutations result in various pain phe- bENaC flox/flox and Advillin-Cre/gENaC flox/flox mice notypes in humans [17]. Two mutant mouse strains using the Hargreaves test and was shown to be unal- with targeted ablation of Nav1.8, Nav1.7 or both, exhibit tered (Figure 1c, g). Motor coordination was also found an unequivocal insensitivity to painful mechanical pres- to be unaffected by deletion of b-andg subunits in sure while retaining the ability to sense low threshold DRG neurons (Figure 1d, h). mechanical stimuli [18]. Voltage gated sodium channels Altogether the results gathered from the behavioural have been shown to be mechanosensitive. Nav 1.4 and assessment of mice in which b and g ENaC channels were Nav1.6 have been reported to respond to mechanical sti- knocked out in DRG neurons reveal no obvious role for mulation (stretch) by irreversible hyperpolarizing shift in these channels in either acute pain or somatosensation. voltage dependence [19-21]. The Nav1.5 subtype Nav1.7/Nav1.8 double knockout (DKO) mice have ele- responds to mechanical stretch by changes in voltage vated noxious mechanical thresholds but Nav1.7 and dependence of the channel, but the changes are reversi- Nav1.8 are dispensable for mechanically activated currents ble [19]. We sought to investigate the possibility that in DRG neurons Nav1.7 and Nav1.8 might also contribute to noxious We had previously reported the phenotype of the mechanosensation. Nav1.8/Nav1.7 double knockout (SCN10Acre/cre:SCN9A- Here we used knockout mice to determine the contri- flox/flox) mice which are refractory to noxious pressure [18]. bution of sodium channels to mechanotransduction. We The removal of Nav1.7 from nociceptors results in a small show that deletion of b and g ENaC subunits does not reduction in the TTX-sensitive and no change in TTX- alter acute mechanical or thermal pain thresholds. We resistant current densities. However, the input to the layer show that transduction of mechanical stimuli in isolated V wide dynamic range neurons in the spinal cord was sub- sensory neurons is unaffected by the absence of Nav1.8 stantially decreased upon noxious mechanical stimulation and Nav1.7 channels and that the inability to fire action [24]. This raises the possibility that Nav1.7 and Nav1.8 are potentials is likely the basis of the behavioural deficits in part of mechanotransduction protein complex, indepen- mechanosensation observed in these mice. dent of their Nav channel function, and that they could be needed for the proper assembly or targeting of the noxious Results force transducer to the membrane or that they are trans- ENaC b- and g subunit null mutant mice have normal ducers themselves. DRG neurons in culture respond to acute noxious sensory thresholds mechanical stimulation of the soma or neurites by eliciting b and g ENaC subunits are expressed in all types of DRG inward mechanically activated (MA) currents [2,25,26]. In neurons [14,15,22]. Noxious (high threshold) mechanosen- mouse DRG cultures, 50 to 60% of neurons are responsive sation is sensed by small nociceptive Nav1.8-expressing to mechanical stimulation (depending on the recording DRG neurons [23]. To assess the possible role of b and g configuration) under patch clamp recording conditions ENaC in noxious mechanosensation, we therefore deleted (data not shown but see reference [7]). Three types of MA them in Nav1.8-positive nociceptors using the Nav1.8-Cre currents are observed in response to focal stimulation; mouse crossed to bENaC flox/flox and gENaC flox/flox mice. rapidly inactivating (RA) currents that are thought to cor- Nociceptor-specific ENaC-null mice did not exhibit any relate with low threshold mechanotransducers, intermedi- deficit in the Randall-Selitto test of mechanical pain ate and slow inactivating currents (IA and SA) that (Figure 1a, e), suggesting that b-andg ENaCs are not correlate with higher threshold mechanotransducers [2]. implicated in the transduction of painful mechanical We have shown that NMB1,
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