| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Topical Review |
1 NeuroSolutions Ltd, PO Box 3517, Coventry CV4 7ZS, UK
2 Department of Pharmacology and Toxicology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
3 Department of Neurology and Center for Neuroscience & Regeneration Research, Yale University School of Medicine, New Haven, CT 06510, USA
4 Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT 06516, USA
 |
Abstract |
|---|
 Top Abstract References |
|---|
(Received 20 September 2006;
accepted after revision 6 December 2006;
first published online 7 December 2006)
Corresponding author S. G. Waxman: Yale University School of Medicine, 333 Cedar Street, LCI 707, New Haven, CT 06510, USA and A. M. Rush: NeuroSolutions Ltd, PO Box 3517, Coventry CV4 7ZS, UK. Email: stephen.waxman{at}yale.edu and trush{at}neurosolutionsltd.com
Introduction
Although electrogenesis in neurons has classically been considered to be the product of activity of ‘the’ sodium channel, we now know that multiple isoforms of voltage-gated sodium channels (Nav) are present within neurons (Catterall et al. 2005). It is becoming increasingly clear that these multiple sodium channel isoforms collaborate in the production of electrical activity by neurons. Particularly fruitful for the study of sodium channels and their roles in electrogenesis are the neurons of the dorsal root ganglia (DRG), a collection of cell bodies of the afferent sensory fibres, which lie between adjacent vertebrae. The soma of the DRG neuron is spherical, and is located on a side branch of the main axon (receiving little synaptic input) and its isolation for techniques such as patch-clamp is relatively easy and can provide excellent recording conditions, making it an especially tractable model neuron. Additionally, changes in excitability of DRG neurons are of importance in a number of pathological conditions. Our understanding of the very different roles particular sodium channels play in influencing excitability of DRG neurons has progressed rapidly. In this review, we examine the roles of sodium channels in the excitability of DRG neurons.
Multiple sodium channel subtypes within DRG neurons
Conduction velocity of the dorsal root fibres has been associated with DRG cell size, classifying these neurons into four main groups: A
, 30–55 m s–1; A
, 14–30 m s–1; A
, 2.2–8 m s–1; and C, <1.4 m s–1 (Harper & Lawson, 1985a,b). These fibres relay information from muscle and skeletal mechanoreceptors (A, A), cutaneous and subcutaneous mechanoreceptors (A, A) and nociceptors (A, C). The slower velocity fibres are generally associated with small cells, and the action potential duration is broader, often displaying an inflection or hump on the falling phase. Many of these characteristics have now been associated with expression of particular sodium channel subtypes in specific subclasses of DRG neurons. Studies of C-fibres (e.g. from sciatic nerve) have shown that they can generate a slow sodium-dependent spike that is resistant to tetrodotoxin (TTX), due to the presence of TTX-resistant (TTX-R) sodium channels (Gaumann et al. 1992; Kobayashi et al. 1993; Jeftinija, 1994; Buchanan et al. 1996) and, subsequently, to the specific isoform responsible for the current, Nav1.8 (Akopian et al. 1996; Sangameswaran et al. 1996). Multiple studies have now shown that there are large variations in sodium current parameters in DRG neurons, linked to expression of a heterogeneous population of sodium channels (as summarized in Table 1; Kostyuk et al. 1981; Caffrey et al. 1992; Roy & Narahashi, 1992; Elliott & Elliott, 1993; Ogata & Tatebayashi, 1993; Rizzo et al. 1994; Rush et al. 1998; Cummins et al. 1999). Apart from pharmacological intervention using TTX, one can dissect the channels by using parallel methods of immunohistochemistry and electrophysiological recording, giving insight into the expression patterns and possible roles of the various channel isoforms. Using immunocytochemical techniques, large DRG cells have been shown to predominantly express TTX-sensitive (TTX-S) channels, such as Nav1.1, Nav1.6 and Nav1.7, with some TTX-R Nav1.8 expression (Black et al. 1996). Small cells, which are likely to be nociceptive in nature, express TTX-S channels (Black et al. 1996; Sangameswaran et al. 1997; Toledo-Aral et al. 1997), in conjunction with TTX-R Nav1.8 and Nav1.9 channels (Amaya et al. 2000; Fjell et al. 2000). These findings have been further corroborated using intracellular recording, together with immunohistochemistry, to show the distribution of channels in DRG neurons that give rise to particular fibre types (Fang et al. 2002, 2006; Djouhri et al. 2003a,b). Although it is not known whether the complement of sodium channels along, or at the terminals of, an axon are the same as at the cell body giving rise to that fibre, it is known that expression of multiple sodium channels, including TTX-R channels, is not limited to the cell body and extends along the fibres (Brock et al. 1998; Strassman & Raymond, 1999; Black et al. 2002a; Black & Waxman, 2002b; Rush et al. 2005a, 2006b), demonstrating the likely importance of these channels in conduction and fibre characteristics.
|
Trafficking and expression of sodium channels can be regulated by association of channels with cofactors, in many cases in an isoform-specific manner. In DRG neurons, one such protein is annexin II/p11, which binds to the N-terminus of Nav1.8 and facilitates insertion of functional Nav1.8 channels into the cell membrane (Okuse et al. 2002). CAP-1A, a linker protein that binds clathrin and Nav1.8, plays a complementary role, removing Nav1.8 channels from the cell membrane (Liu et al. 2005). Contactin, a glycosyl-phosphatidylinositol (GPI)-anchored neuronal surface glycoprotein (Ranscht, 1988; Brummendorf et al. 1989; Gennarini et al. 1989), has been found to interact with Nav1.2 via the 1-subunit and increases channel density at the plasma membrane in heterologous cells (Kazarinova-Noyes et al. 2001; Chen et al. 2004) and produces similar effects with Nav1.3 and Nav1.9 (Liu et al. 2001; Shah et al. 2004). In DRG neurons, contactin has been found to regulate current density of TTX-R sodium channels Nav1.8 and Nav1.9 in the subset of largely nociceptive, -D-galactosyl lectin-binding IB4+ neurons, although TTX-S channels (Nav1.6 and Nav1.7) were unaffected (Rush et al. 2005a). TTX-S channels may instead be regulated by 2 subunits and this interaction has been shown to modulate the response to pain (Pertin et al. 2005; Lopez-Santiago et al. 2006). However, contactin may also play a role in the pathological re-emergence of Nav1.3 in adult DRG neurons and accumulation of the channel in the neuroma of transected sciatic nerve (Shah et al. 2004). In addition to affecting plasma membrane channel density, the activation and inactivation kinetics of TTX-S currents are accelerated by 2, and other -subunits are involved in modulation of Nav1.8 (Shah et al. 2000; Vijayaragavan et al. 2004). Although some proteins may function primarily or solely as channel chaperones, such as annexin II/p11 with Nav1.8 (Okuse et al. 2002), alteration of biophysical parameters can also occur with other cofactors. Fibroblast growth factor homologous factor (FHF) 2A and 2B have been demonstrated to be present in DRG neurons, and associate with Nav1.6 to increase current density but also modulate the channel's biophysical properties, for instance, depolarizing steady-state inactivation (Wittmack et al. 2004; Rush et al. 2006b). Calmodulin can bind to the C-terminus of sodium channels (Herzog et al. 2003b) and can also modulate both the current density and biophysical properties of sodium currents generated by Nav1.6 and Nav1.8 in DRG neurons (Herzog et al. 2003b; Choi et al. 2006). Several of these proteins have been demonstrated to be coexpressed with their target interacting sodium channel, not only in the cell body but also along the nerve fibre (Wittmack et al. 2004; Liu et al. 2005; Rush et al. 2005a, 2006b). Thus, there are multiple sodium channel associated proteins in DRG neurons and associated fibres that control not only the density of different channel isoforms at the membrane but also some of the biophysical properties of the channels themselves.
Activation and inactivation characteristics
The slowly TTX-R inactivating sodium channel, now known to be Nav1.8, which is specifically expressed within DRG and trigeminal neurons (Akopian et al. 1996; Sangameswaran et al. 1996), has more depolarized steady-state activation and inactivation (Fig. 1) characteristics than the TTX-S channels (Kostyuk, 1981; Caffrey et al. 1992; Roy & Narahashi, 1992; Elliott & Elliott, 1993; Ogata & Tatebayashi, 1993; Rizzo et al. 1994; Cummins & Waxman, 1997; Rush et al. 1998). DRG neurons are thus rather unique in having a mix of channels with an unusually wide range of varied characteristics. As we will see throughout this review, it has been possible over the last few years to examine the specific roles of different sodium channel isoforms in the firing behaviour of DRG neurons. Using knock-out mice, Nav1.8 channels were shown to be essential for generation of single action potentials in most small DRG neurons and in fact generate about 80% of the inward current underlying the action potential upstroke in these cells (Renganathan et al. 2001). When Nav1.8 was absent, the more hyperpolarized voltage-dependent properties of the TTX-S channels were revealed by inhibition of firing with even minor depolarization (Fig. 2). Although TTX-R channels are the major contributor to the action potential upstroke, TTX-S channels also play a significant part, especially around threshold, with a relatively minor involvement of high threshold calcium channels (Blair & Bean, 2002). The depolarized voltage dependence of inactivation of Nav1.8, together with rapid recovery from inactivation (see below), also allows repetitive firing with sustained depolarization (Fig. 3) (Renganathan et al. 2001; Blair & Bean, 2003).
|
|
|
Repriming: recovery from inactivation
Several recent studies have shed light on the distinct patterns of recovery from inactivation (repriming) of the different sodium channel isoforms in DRG neurons. The TTX-S currents of intact large DRG neurons tend to have relatively fast repriming characteristics (Cummins & Waxman, 1997; Everill et al. 2001), which correlates with expression in these neurons of Nav1.6 (Black et al. 1996), an isoform that displays this characteristic when expressed and studied in isolation in DRG (Herzog et al. 2003a; Rush et al. 2005b). In contrast, TTX-S currents in uninjured small DRG neurons, which include nociceptors, tend to have slow repriming (Elliott & Elliott, 1993; Cummins & Waxman, 1997; Rush et al. 1998; Black et al. 1999), similar to the behaviour of Nav1.7 when expressed in cell lines or in a DRG background (Cummins et al. 1998; Herzog et al. 2003a). From this evidence, differential expression of Nav1.6 or Nav1.7 appears to endow these neurons with distinct TTX-S repriming properties. However, Nav1.6 is expressed in all DRG cell sizes, including small cells giving rise to unmyelinated fibres (Black et al. 2002a; Rush et al. 2005a) and Nav1.7 is also expressed in most DRG cells (Sangameswaran et al. 1997; Toledo-Aral et al. 1997). One possible explanation for this apparent discrepancy is that there are differences in the amount of non-functional channel protein for Nav1.6 and Nav1.7 channels in small and large DRG neurons. An alternative explanation is that functional properties of Nav1.6 and/or Nav1.7 are modified by other factors, such as associated proteins or kinases, that are differentially expressed in specific populations of DRG neurons. One likely candidate is fibroblast growth factor homologous factor 2A (FHF2A). This protein associates with Nav1.6 via the C-terminus of the channel, is present in DRG neurons and strongly inhibits repriming of Nav1.6, leading to a large accumulation of inactivation during repetitive stimulation (Rush et al. 2006b). Expression of FHF2A in small DRG neurons may help explain the anomalous repriming and channel expression observation outlined above. In addition, there may be as yet unknown cofactors that accelerate repriming of Nav1.7 in larger DRG neurons. An emerging trend (see Cummins et al. 2001) is that the cellular background in which particular channels are expressed is an important determinant of the behaviour of sodium channel isoforms.
Recovery from inactivation is a critical channel characteristic that also plays a role in nerve injury. Chronic constriction injury (CCI) and axotomy of the sciatic nerve both trigger a down-regulation of Nav1.8 and Nav1.9 and an up-regulation of Nav1.3 expression in nociceptive DRG neurons (Waxman et al. 1994; Dib-Hajj et al. 1996; Cummins & Waxman, 1997; Dib-Hajj et al. 1998; Cummins et al. 2000; Kim et al. 2002) that is accompanied by the emergence of a rapidly repriming TTX-S current in these cells (Fig. 4) (Cummins & Waxman, 1997). Nav1.3 is normally only expressed during early stages of development and is practically undetectable in the adult rat nervous system (Beckh et al. 1989; Waxman et al. 1994; Felts et al. 1997). The change in channel expression is likely to be due to reduced access of axotomized DRG neurons to peripheral pools of neurotrophic factors such as nerve growth factor (NGF) and glial derived neurotrophic factor (GDNF), as the effects can be reversed by increasing their levels after nerve injury (Dib-Hajj et al. 1998; Fjell et al. 1999; Boucher et al. 2000; Cummins et al. 2000; Leffler et al. 2002).
|
|
In addition to fast inactivation, DRG sodium channels can also undergo slow inactivation (Ogata & Tatebayashi, 1992; Rush et al. 1998), a process that occurs over a longer time course. The mechanism is thought to be separate from the III–IV linker associated with fast inactivation, as the phenomenon is maintained in channels of squid axon, despite removal of fast inactivation with pronase (Rudy, 1978). The exact structural rearrangements are still being elucidated, and appear to involve many different regions of the channel (for reviews see Goldin, 2003; Ulbricht, 2005). Interestingly, different sodium channel isoforms undergo different levels of slow inactivation (Vilin et al. 2001) and thus the mixed populations of channels in DRG neurons are likely to be affected differently by RMP and periods of depolarization. In comparisons of small DRG TTX-S and TTX-R currents, despite the more depolarized fast inactivation characteristics, TTX-R channels had quicker and much more complete slow inactivation at depolarized voltages (Rush et al. 1998; Blair & Bean, 2003) and this perhaps explains the differential block by agents sometimes used in the treatment of neuropathic pain, such as phenytoin and carbamazapine (Rush & Elliott, 1997; Cardenas et al. 2006). The midpoint of TTX-R slow inactivation is actually more hyperpolarized than that for fast inactivation (Blair & Bean, 2003), in marked contrast to the reverse situation commonly found for TTX-S currents (Kuo & Bean, 1994; Fleidervish et al. 1996; Fazan et al. 2001). Build-up of slow inactivation is likely to be responsible for the use-dependent inhibition of TTX-R currents on repetitive stimulation (Rush et al. 1998; Blair & Bean, 2003; Tripathi et al. 2006) and the cell-to-cell variations in TTX-R current properties seen in these studies might reflect regulation of Nav1.8 by calmodulin (Choi et al. 2006). Interestingly, use-dependent slow inactivation of Nav1.8 current is stronger and develops more rapidly in IB4+ DRG neurons, compared to IB4– DRG neurons, and recovery from slow inactivation is slower in IB4+ neurons (Choi et al. 2007), adding to evidence (Stucky & Lewin, 1999; Braz et al. 2005; Fang et al. 2006) that these subclasses of DRG neurons are functionally distinct.
Resurgent current
Current that occurs upon repolarization is termed resurgent current and was first recorded from cerebellar Purkinje neurons (Raman & Bean, 1997a). It is a transient current that displays slow re-activation and inactivation upon rapid repolarization. Initially, resurgent current was linked with the presence of Nav1.6 in Purkinje neurons (Raman et al. 1997b). Evidence to date suggests that at least some subpopulations of DRG neurons can produce resurgent current (Cummins et al. 2005; Rush et al. 2005b). About 60% of DRG neurons transfected with Nav1.6 produce resurgent currents attributable to this channel (Cummins et al. 2005). Other studies have led to the suggestion that other sodium channel isoforms may also be able to produce a resurgent current as it can be recorded from neurons that do not express Nav1.6 (Afshari et al. 2004; Do & Bean, 2004). In line with this is the observation that approximately 8% of DRG neurons transfected with Nav1.2 can produce resurgent current attributable to this channel isoform (Rush et al. 2005b).
With normal channel isoform expression in the adult, the resurgent current may be limited to large DRG neurons (Cummins et al. 2005). The cofactor(s) that permit Nav1.6 and Nav1.2 to produce resurgent current in some cell types, but not in others, are still under study. Phosphorylation of the sodium channels may play a role (Grieco et al. 2002) and open channel block by the sodium channel 4 subunit appears to be involved, for the Nav1.6 channel at least (Grieco et al. 2005). The specific role of the resurgent current in DRG neurons has still to be elucidated but in other neurons it has been associated with rapid burst firing in response to large depolarizations (Raman & Bean, 1997a; Khaliq et al. 2003; Swensen & Bean, 2003; Magistretti et al. 2006).
Ramp currents
As we have discussed, Nav1.8 carries a current that has very depolarized voltage dependence of activation and inactivation and is extremely resistant to depolarization. However, TTX-S currents do still play a role in the action potential, especially around threshold (Blair & Bean, 2002). Nav1.7 is one of the major candidates that has been suggested to amplify subthreshold generator potentials by producing a prominent ramp current (response to small, slow depolarizing stimuli), largely due to its slow onset of closed-state inactivation (Cummins et al. 1998). It is thought that under conditions where there is slow depolarization of a neuron, this particular channel would tend to remain available for activation, in comparison with other channels that are able to activate only at relatively hyperpolarized potentials. This property would be predicted to make Nav1.7 a significant source of ramp currents and this isoform has indeed been shown to produce a robust ramp current in response to slow depolarizations (Cummins et al. 1998; Herzog et al. 2003a) (see Fig. 6). More recently, mutations in Nav1.7, associated with the neuropathic pain syndrome erythromelalgia (Cummins et al. 2004; Yang et al. 2004; Dib-Hajj et al. 2005; Drenth et al. 2005; Han et al. 2005), have helped to demonstrate its role as a threshold channel that can interact with Nav1.8 to produce hyperexcitability and repetitive firing behaviour of nociceptive neurons (Dib-Hajj et al. 2005; Rush et al. 2006a). Nav1.7 appears to bring the neuron closer to the potential needed for activation of Nav1.8, thereby increasing excitability. In marked contrast, when the effects of an erythromelalgia mutation were examined in a cell type that lacks Nav1.8 (sympathetic ganglion neurons), a reduction in excitability was seen (Rush et al. 2006a), presumably due to inactivation of the TTX-S sodium channels essential for the action potential upstroke in those neurons. Subsequent addition of Nav1.8 into sympathetic neurons allowed these cells to fire action potentials despite depolarization of resting membrane potential induced by the mutant Nav1.7 channels, demonstrating how sodium channel isoforms with different biophysical characteristics can interact with one another (Fig. 7). These data may help to explain both the pain caused by mild stimulation (due to hyperexcitability of nociceptive DRG neurons) and also the sympathetic dysfunction associated with this disorder (flushing of the extremities due to loss of vasoconstrictive tone) which is due to hypoexcitability of sympathetic ganglion neurons (Rush et al. 2006a).
|
|
Sodium channel combinations and interactions
Thus far, we have discussed many of the specific biophysical characteristics that define particular sodium channel isoforms, how they behave in the DRG neuron background and what their individual influence may be on the neurons and neuronal processes where they are expressed. However, in some conditions, there are not only long-term chronic changes in expression of multiple sodium channels, but also shorter term acute alterations in behaviour of existing channels, in response to changes in their environment. Thus, in order to understand the overall likely effects on firing behaviour, it is important to consider how the rise in expression of one channel or change in biophysical characteristics of another might relate to each other. For example, in models of inflammatory pain such as carrageenan injection into the hindpaw there is an up-regulation of TTX-S channels Nav1.3 and Nav1.7 in DRG after a few days, together with a parallel increase in the TTX-S current (Black et al. 2004). This is in addition to an increased expression of Nav1.8 and a boosted TTX-R current (Tanaka et al. 1998; Black et al. 2004). In contrast, expression of Nav1.6 and Nav1.9 are relatively unaffected in the inflammatory response. These changes might amplify previously subthreshold inputs (due to up-regulation of Nav1.3 and Nav1.7) and help in sustaining repetitive firing under prolonged depolarization (Nav1.3 and Nav1.8).
Nav1.8 is also likely to be involved in acute inflammatory pain as administration of agents such as prostaglandin E2 (PGE2) and 5-HT produces an increase in current amplitude and a hyperpolarizing shift in activation, both likely to increase excitability (England et al. 1996; Gold et al. 1996; Cardenas et al. 1997, 2001). Recent evidence also points towards the involvement of Nav1.9 in the inflammatory response. Acute administration of inflammatory mediator PGE2 causes a large increase in the amplitude of Nav1.9 (Rush & Waxman, 2004), a channel which, when knocked out in the mouse, produces deficits in the inflammatory response but not in neuropathic pain models (Priest et al. 2005). These data suggest that Nav1.9 may play a significant role in the increased excitability of nociceptive fibres during inflammation, either by effects on resting potential, by sustaining depolarization, or by lowering threshold (Herzog et al. 2001; Baker et al. 2003). However, in another inflammatory model, induced jejunitis was linked to changes in Nav1.8 but knocking out Nav1.9 had no effect (Hillsley et al. 2006). There is still much to be done to fully understand the intricate roles of sodium channel isoforms in the variety of pain models and to translate these results to the clinic.
Overview: does complexity of sodium channel expression represent a therapeutic opportunity?
Although the expression of an especially large repertoire of sodium channel isoforms makes DRG neurons complex, the accessibility and spherical shape of the these cells, and their involvement in a number of readily modelled disease states involving sodium channels, have made them a very tractable model for the study of the roles of sodium channels in electrogenesis. Excitability of DRG neurons can be affected by changes during development and a variety of pathologies and injuries. Sodium channels, which were once thought to be uniform in terms of biophysical properties and simply responsible for the rising phase of an action potential, have now been shown to be able to play multiple roles in electrogenesis, and thus can finely tune the behaviour of excitable cells. The presence of multiple sodium channel isoforms within DRG neurons suggests the possibility of pharmacologically targeting specific channel subtypes, thus possibly achieving therapeutic activity whilst limiting undesirable side-effects. Changes in expression levels or physiological properties of specific sodium channel isoforms are likely to contribute to altered function of DRG neurons in a variety of pathologies and these isoforms may therefore be tractable targets for subtype specific modulators.
|
References |
|---|
|
TopAbstractReferences |
|---|
Akopian AN, Sivilotti L & Wood JN (1996). A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature 379, 257–262.[CrossRef][Medline]
Amaya F, Decosterd I, Samad TA, Plumpton C, Tate S, Mannion RJ, Costigan M & Woolf CJ (2000). Diversity of expression of the sensory neuron-specific TTX-resistant voltage-gated sodium ion channels SNS and SNS2. Mol Cell Neurosci 15, 331–342.[CrossRef][Medline]
Attwell D, Cohen I, Eisner D, Ohba M & Ojeda C (1979). The steady-state TTX-S ‘window’ sodium current in cardiac purkinje fibres. Pfugers Arch 379, 137–142.[CrossRef][Medline]
Baker MD, Chandra SY, Ding Y, Waxman SG & Wood JN (2003). GTP-induced tetrodotoxin-resistant Na+ current regulates excitability in mouse and rat small diameter sensory neurones. J Physiol 548, 373–382.
Beckh S, Noda M, Lübbert H & Numa S (1989). Differential regulation of three sodium channel messenger RNAs in the rat central nervous system during development. EMBO J 8, 3611–3616.[Medline]
Black JA, Cummins TR, Plumpton C, Chen YH, Hormuzdiar W, Clare JJ & Waxman SG (1999). Upregulation of a silent sodium channel after peripheral, but not central, nerve injury in DRG neurons. J Neurophysiol 82, 2776–2785.
Black JA, Dib-Hajj S, McNabola K, Jeste S, Rizzo MA, Kocsis JD & Waxman SG (1996). Spinal sensory neurons express multiple sodium channel -subunit mRNAs. Mol Brain Res 43, 117–131.[Medline]
Black JA, Liu S, Tanaka M, Cummins TR & Waxman SG (2004). Changes in the expression of tetrodotoxin-sensitive sodium channels within dorsal root ganglia neurons in inflammatory pain. Pain 108, 237–247.[CrossRef][Medline]
Black JA, Renganathan M & Waxman SG (2002a). Sodium channel Nav1.6 is expressed along nonmyelinated axons and it contributes to conduction. Mol Brain Res 105, 19–28.[Medline]
Black JA & Waxman SG (2002b). Molecular identities of two tetrodotoxin-resistant sodium channels in corneal axons. Exp Eye Res 75, 193–199.[CrossRef][Medline]
Blair NT & Bean BP (2002). Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons. J Neurosci 22, 10277–10290.
Blair NT & Bean BP (2003). Role of tetrodotoxin-resistant Na+ current slow inactivation in adaptation of action potential firing in small-diameter dorsal root ganglion neurons. J Neurosci 23, 10338–10350.
Boucher TJ, Okuse K, Bennett DL, Munson JB, Wood JN & McMahon SB (2000). Potent analgesic effects of GDNF in neuropathic pain states. Science 290, 124–127.
Braz JM, Nassar MA, Wood JN & Basbaum AL (2005). Parallel ‘pain’ pathways arise from subpopulations of primary afferent nociceptor. Neuron 47, 787–793.[CrossRef][Medline]
Brock JA, McLachlan EM & Belmonte C (1998). Tetrodotoxin-resistant impulses in single nociceptor nerve terminals in guinea-pig cornea. J Physiol 512, 211–217.
Brummendorf T, Wolff JM, Frank R & Rathjen FG (1989). Neural cell recognition molecule F11: homology with fibronectin type III and immunoglobulin type C domains. Neuron 2, 1351–1361.[CrossRef][Medline]
Buchanan S, Harper AA & Elliott JR (1996). Differential effects of tetrodotoxin (TTX) and high external K+ on A and C fibre compound action potential peaks in frog sciatic nerve. Neurosci Lett 219, 131–134.[CrossRef][Medline]
Caffrey JM, Eng DL, Black JA, Waxman SG & Kocsis JD (1992). Three types of sodium channels in adult rat dorsal root ganglion neurons. Brain Res 592, 283–297.[CrossRef][Medline]
Cardenas CA, Cardenas CG, de Armendi AJ & Scroggs RS (2006). Carbamazepine interacts with a slow inactivation state of Nav1.8 like sodium channels. Neurosci Lett 408, 129–134.[CrossRef][Medline]
Cardenas LM, Cardenas CG & Scroggs RS (2001). 5HT increases excitability of nociceptor-like rat dorsal root ganglion neurons via cAMP-coupled TTX-resistant Na+ channels. J Neurophysiol 86, 241–248.
Cardenas CG, Del Mar LP, Cooper BY & Scroggs RS (1997). 5HT4 receptors couple positively to tetrodotoxin-insensitive sodium channels in a subpopulation of capsaicin-sensitive rat sensory neurons. J Neurosci 17, 7181–7189.
Catterall WA, Goldin AL & Waxman SG (2005). International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev 57, 397–409.
Chen C, Westenbroek RE, Xu X, Edwards CA, Sorenson DR, Chen Y, McEwen DP, O'Malley HA, Bharucha V, Meadows LS, Knudsen GA, Vilaythong A, Noebels JL, Saunders TL, Scheuer T, Shrager P, Catterall WA & Isom LL (2004). Mice lacking sodium channel beta1 subunits display defects in neuronal excitability, sodium channel expression, and nodal architecture. J Neurosci 24, 4030–4042.
Choi JS, Dib-Hajj SD & Waxman SG (2007). Differential slow inactivation and use-dependent inhibition of Nav1.8 channels contribute to distinct firing properties in IB4+ DRG neurons. J Neurophysiol doi: 10.1152/jn.01033.2006 (in press).
Choi JS, Hudmon A, Waxman SG & Dib-Hajj SD (2006). Calmodulin regulates current density and frequency-dependent inhibition of sodium channel Nav1.8 in DRG neurons. J Neurophysiol 96, 97–108.
Cummins TR, Aglieco F, Renganathan M, Herzog RI, Dib-Hajj SD & Waxman SG (2001). Nav1.3 sodium channels: rapid repriming and slow closed-state inactivation display quantitative differences after expression in a mammalian cell line and in spinal sensory neurons. J Neurosci 21, 5952–5961.
Cummins TR, Black JA, Dib-Hajj SD & Waxman SG (2000). Glial-derived neurotrophic factor upregulates expression of functional SNS and NaN sodium channels and their currents in axotomized dorsal root ganglion neurons. J Neurosci 20, 8754–8761.
Cummins TR, Dib-Hajj SD, Black JA, Akopian AN, Wood JN & Waxman SG (1999). A novel persistent tetrodotoxin-resistant sodium current in SNS-null and wild-type small primary sensory neurons. J Neurosci 19, RC43.
Cummins TR, Dib-Hajj SD, Herzog RI & Waxman SG (2005). Nav1.6 channels generate resurgent sodium currents in spinal sensory neurons. FEBS Lett 579, 2166–2170.[CrossRef][Medline]
Cummins TR, Dib-Hajj SD & Waxman SG (2004). Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy. J Neurosci 24, 8232–8236.
Cummins TR, Howe JR & Waxman SG (1998). Slow closed-state inactivation: a novel mechanism underlying ramp currents in cells expressing the hNE/PN1 sodium channel. J Neurosci 18, 9607–9619.
Cummins TR & Waxman SG (1997). Downregulation of tetrodotoxin-resistant sodium currents and upregulation of a rapidly repriming tetrodotoxin-sensitive sodium current in small spinal sensory neurons after nerve injury. J Neurosci 17, 3503–3514.
Dib-Hajj S, Black JA, Felts P & Waxman SG (1996). Down-regulation of transcripts for Na channel -SNS in spinal sensory neurons following axotomy. Proc Natl Acad Sci U S A 93, 14950–14954.
Dib-Hajj SD, Rush AM, Cummins TR, Hisama FM, Novella S, Tyrrell L, Marshall L & Waxman SG (2005). Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons. Brain 128, 1847–1854.
Dib-Hajj SD, Tyrrell L, Black JA & Waxman SG (1998). NaN, a novel voltage-gated Na channel, is expressed preferentially in peripheral sensory neurons and down-regulated after axotomy. Proc Natl Acad Sci U S A 95, 8963–8968.
Djouhri L, Fang X, Okuse K, Wood JN, Berry CM & Lawson SN (2003a). The TTX-resistant sodium channel Nav1.8 (SNS/PN3): expression and correlation with membrane properties in rat nociceptive primary afferent neurons. J Physiol 550, 739–752.
Djouhri L, Newton R, Levinson SR, Berry CM, Carruthers B & Lawson SN (2003b). Sensory and electrophysiological properties of guinea-pig sensory neurones expressing Nav1.7 (PN1) Na+ channel -subunit protein. J Physiol 546, 565–576.
Do MT & Bean BP (2004). Sodium currents in subthalamic nucleus neurons from Nav1.6-null mice. J Neurophysiol 92, 726–733.
Drenth JP, te Morsche RH, Guillet G, Taieb A, Kirby RL & Jansen JB (2005). SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels. J Invest Dermatol 124, 1333–1338.[CrossRef][Medline]
Elliott AA & Elliott JR (1993). Characterization of TTX-sensitive and TTX-resistant sodium currents in small cells from adult rat dorsal root ganglia. J Physiol 463, 39–56.
England S, Bevan S & Docherty RJ (1996). PGE2 modulates the tetrodotoxin-resistant sodium current in neonatal rat dorsal root ganglion neurones via the cyclic AMP-protein kinase A cascade. J Physiol 495, 429–440.[Medline]
Everill B, Cummins TR, Waxman SG & Kocsis JD (2001). Sodium currents of large (A-type) adult cutaneous afferent dorsal root ganglion neurons display rapid recovery from inactivation before and after axotomy. Neuroscience 106, 161–169.[CrossRef][Medline]
Fang X, Djouhri L, Black JA, Dib-Hajj SD, Waxman SG & Lawson SN (2002). The presence and role of the tetrodotoxin-resistant sodium channel Nav1.9 (NaN) in nociceptive primary afferent neurons. J Neurosci 22, 7425–7433.
Fang X, Djouhri L, McMullan S, Berry C, Waxman SG, Okuse K & Lawson SN (2006). Intense isolectin-B4 binding in rat dorsal root ganglion neurons distinguishes C-fiber nociceptors with broad action potentials and high Nav1.9 expression. J Neurosci 26, 7281–7292.
Fazan R Jr, Whiteis CA, Chapleau MW, Abboud FM & Bielefeldt K (2001). Slow inactivation of sodium currents in the rat nodose neurons. Auton Neurosci 87, 209–216.[CrossRef][Medline]
Felts PA, Yokoyama S, Dib-Hajj S, Black JA & Waxman SG (1997). Sodium channel -subunit mRNAs I, II, III, NaG, Na6 and HNE (PN1) – different expression patterns in developing rat nervous system. Mol Brain Res 45, 71–82.[Medline]
Fjell J, Cummins TR, Dib-Hajj SD, Fried K, Black JA & Waxman SG (1999). Differential role of GDNF and NGF in the maintenance of two TTX- resistant sodium channels in adult DRG neurons. Mol Brain Res 67, 267–282.[Medline]
Fjell J, Hjelmstrom P, Hormuzdiar W, Milenkovic M, Aglieco F, Tyrrell L, Dib-Hajj S, Waxman SG & Black JA (2000). Localization of the tetrodotoxin-resistant sodium channel NaN in nociceptors. Neuroreport 11, 199–202.[Medline]
Fleidervish IA, Friedman A & Gutnick MJ (1996). Slow inactivation of Na+ current and slow cumulative spike adaptation in mouse and guinea-pig neocortical neurones in slices. J Physiol 493, 83–97.[Medline]
Gaumann DM, Brunet PC & Jirounek P (1992). Clonidine enhances the effects of lidocaine on C-fiber action potential. Anesthesis Analgesia 74, 719–725.
Gennarini G, Cibelli G, Rougon G, Mattei MG & Goridis C (1989). The mouse neuronal cell surface protein F3: a phosphatidylinositol- anchored member of the immunoglobulin superfamily related to chicken contactin. J Cell Biol 109, 775–788.
Gold MS, Reichling DB, Shuster MJ & Levine JD (1996). Hyperalgesic agents increase a tetrodotoxin-resistant Na+ current in nociceptors. Proc Natl Acad Sci U S A 93, 1108–1112.
Goldin AL (2003). Mechanisms of sodium channel inactivation. Curr Opin Neurobiol 13, 284–290.[CrossRef][Medline]
Grieco TM, Afshari FS & Raman IM (2002). A role for phosphorylation in the maintenance of resurgent sodium current in cerebellar purkinje neurons. J Neurosci 22, 3100–3107.
Grieco TM, Malhotra JD, Chen C, Isom LL & Raman IM (2005). Open-channel block by the cytoplasmic tail of sodium channel 4 as a mechanism for resurgent sodium current. Neuron 45, 233–244.[CrossRef][Medline]
Han C, Rush AM, Dib-Hajj SD, Li S, Xu Z, Wang Y, Tyrrell L, Wang X, Yang Y & Waxman SG (2005). Sporadic onset of erythermalgia: a gain-of-function mutation in Nav1.7. Ann Neurol 59, 553–558.[CrossRef]
Harper AA & Lawson SN (1985a). Conduction velocity is related to morphological cell type in rat dorsal root ganglion neurones. J Physiol 359, 31–46.
Harper AA & Lawson SN (1985b). Electrical properties of rat dorsal root ganglion neurones with different peripheral nerve conduction velocities. J Physiol 359, 47–63.
Herzog RI, Cummins TR, Ghassemi F, Dib-Hajj SD & Waxman SG (2003a). Distinct repriming and closed-state inactivation kinetics of Nav1.6 and Nav1.7 sodium channels in mouse spinal sensory neurons. J Physiol 551, 741–750.
Herzog RI, Cummins TR & Waxman SG (2001). Persistent TTX-resistant Na+ current affects resting potential and response to depolarization in simulated spinal sensory neurons. J Neurophysiol 86, 1351–1364.
Herzog RI, Liu C, Waxman SG & Cummins TR (2003b). Calmodulin binds to the C terminus of sodium channels Nav1.4 and Nav1.6 and differentially modulates their functional properties. J Neurosci 23, 8261–8270.
Hillsley K, Lin J, Stanisz A, Grundy D, Aerssens J, Peeters P, Moechars D, Coulie B & Stead R (2006). Dissecting the role of sodium currents in visceral sensory neurons in a model of chronic hyperexcitability using Nav1.8 and Nav1.9 null mice. J Physiol 576, 257–267.
Jeftinija S (1994). The role of tetrodotoxin-resistant sodium channels of small primary afferent fibers. Brain Res 639, 125–134.[CrossRef][Medline]
Kazarinova-Noyes K, Malhotra JD, McEwen DP, Mattei LN, Berglund EO, Ranscht B, Levinson SR, Schachner M, Shrager P, Isom LL & Xiao ZC (2001). Contactin associates with Na+ channels and increases their functional expression. J Neurosci 21, 7517–7525.
Khaliq ZM, Gouwens NW & Raman IM (2003). The contribution of resurgent sodium current to high-frequency firing in Purkinje neurons: an experimental and modeling study. J Neurosci 23, 4899–4912.
Kim CH, Oh Y, Chung JM & Chung K (2002). Changes in three subtypes of tetrodotoxin sensitive sodium channel expression in the axotomized dorsal root ganglion in the rat. Neurosci Lett 323, 125–128.[Medline]
Kobayashi J, Ohta M & Terada Y (1993). C fiber generates a slow Na+ spike in the frog sciatic nerve. J Physiol 461, 467–483.
Kostyuk PG, Veselovsky NS & Tsyndrenko AY (1981). Ionic currents in the somatic membrane of rat dorsal root ganglion neurons-I. Sodium currents. Neuroscience 6, 2423–2430.[CrossRef][Medline]
Kuo CC & Bean BP (1994). Slow binding of phenytoin to inactivated sodium channels in rat hippocampal neurons. Mol Pharmacol 46, 716–725.[Abstract]
Lampert A, Hains BC & Waxman SG (2006). Upregulation of persistent and ramp sodium current in dorsal horn neurons after spinal cord injury. Exp Brain Res 174, 660–666.[CrossRef][Medline]
Leffler A, Cummins TR, Dib-Hajj SD, Hormuzdiar WN, Black JA & Waxman SG (2002). GDNF and NGF reverse changes in repriming of TTX-sensitive Na+ currents following axotomy of dorsal root ganglion neurons. J Neurophysiol 88, 650–658.
Lisney SJW & Devor M (1987). Afterdischarge and interactions among fibers in damaged peripheral nerve in the rat. Brain Res 415, 122–136.[CrossRef][Medline]
Liu C, Cummins TR, Tyrrell L, Black JA, Waxman SG & Dib-Hajj SD (2005). CAP-1A is a novel linker that binds clathrin and the voltage-gated sodium channel Nav1.8. Mol Cell Neurosci 28, 636–649.[CrossRef][Medline]
Liu C, Dib-Hajj SD, Black JA, Greenwood J, Lian Z & Waxman SG (2001). Direct interaction with contactin targets voltage-gated sodium channel Nav1.9/NaN to the cell membrane. J Biol Chem 276, 46553–46561.
Lopez-Santiago LF, Pertin M, Morisod X, Chen C, Hong S, Wiley J, Decosterd I & Isom LL (2006). Sodium channel 2 subunits regulate tetrodotoxin-sensitive sodium channels in small dorsal root ganglion neurons and modulate response to pain. J Neurosci 26, 7984–7994.
Magistretti J, Castelli L, Forti L & D'Angelo E (2006). Kinetic and functional analysis of transient, persistent and resurgent sodium currents in rat cerebellar granule cells in situ: an electrophysiological study. J Physiol 573, 83–106.
Matzner O & Devor M (1994). Hyperexcitability at sites of nerve injury depends on voltage-sensitive Na+ channels. J Neurophysiol 72, 349–359.
Morisset V, Randall AD, Davies AJ, Egerton J, Grose DT, Clare JJ, Tate SN, Greem PJ & Gunthorpe M (2005). Functional differences in the behavior of TTX-resistant sodium currents in sensory neurons cultured from WT and Nav1.8 (SNS2) null mice: consequences for neuronal excitability and firing. Soc Neurosci Abstr 31, 622–627.
Ogata N & Tatebayashi H (1992). Slow inactivation of tetrodotoxin-insensitive Na+ channels in neurons of rat dorsal root ganglia. J Membr Biol 129, 71–80.[Medline]
Ogata N & Tatebayashi H (1993). Kinetic analysis of two types of Na+ channels in rat dorsal root ganglia. J Physiol 466, 9–37.
Okuse K, Malik-Hall M, Baker MD, Poon WY, Kong H, Chao MV & Wood JN (2002). Annexin II light chain regulates sensory neuron-specific sodium channel expression. Nature 417, 653–656.[CrossRef][Medline]
Pertin M, Ji RR, Berta T, Powell AJ, Karchewski L, Tate SN, Isom LL, Woolf CJ, Gillard N, Spahn DR & Decosterd I (2005). Upregulation of the voltage-gated sodium channel 2 subunit in neuropathic pain models: characterization of expression in injured and non-injured primary sensory neurons. J Neurosci 25, 10970–10980.
Priest BT, Murphy BA, Lindia JA, Diaz C, Abbadie C, Ritter AM, Liberator P, Iyer LM, Kash SF, Kohler MG, Kaczorowski GJ, MacIntyre DE & Martin WJ (2005). Contribution of the tetrodotoxin-resistant voltage-gated sodium channel Nav1.9 to sensory transmission and nociceptive behavior. Proc Natl Acad Sci U S A 102, 9382–9387.
Raman IM & Bean BP (1997a). Resurgent sodium current and action potential formation in dissociated cerebellar purkinje neurons. J Neurosci 17, 4517–4526.
Raman IM, Sprunger LK, Meisler MH & Bean BP (1997b). Altered subthreshold sodium currents and disrupted firing patterns in Purkinje neurons of Scn8a mutant mice. Neuron 19, 881–891.[CrossRef][Medline]
Ranscht B (1988). Sequence of contactin, a 130-kD glycoprotein concentrated in areas of interneuronal contact, defines a new member of the immunoglobulin supergene family in the nervous system. J Cell Biol 107, 1561–1573.
Renganathan M, Cummins TR & Waxman SG (2001). Contribution of Nav1.8 sodium channels to action potential electrogenesis in DRG neurons. J Neurophysiol 86, 629–640.
Rizzo MA, Kocsis JD & Waxman SG (1994). Slow sodium conductances of dorsal root ganglion neurons: intraneuronal homogeneity and interneuronal heterogeneity. J Neurophysiol 72, 2796–2815.
Roy ML & Narahashi T (1992). Differential properties of tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels in rat dorsal root ganglion neurons. J Neurosci 12, 2104–2111.[Abstract]
Rudy B (1978). Slow inactivation of the sodium conductance in squid giant axons. Pronase resistance. J Physiol 283, 1–21.
Rush AM, Brau ME, Elliott AA & Elliott JR (1998). Electrophysiological properties of sodium current subtypes in small cells from adult rat dorsal root ganglia. J Physiol 511, 771–789.
Rush AM, Craner MJ, Kageyama T, Dib-Hajj SD, Waxman SG & Ranscht B (2005a). Contactin regulates the current density and axonal expression of tetrodotoxin-resistant but not tetrodotoxin-sensitive sodium channels in DRG neurons. Eur J Neurosci 22, 39–49.[CrossRef][Medline]
Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA & Waxman SG (2006a). A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc Natl Acad Sci U S A 103, 8245–8250.
Rush AM, Dib-Hajj SD & Waxman SG (2005b). Electrophysiological properties of two axonal sodium channels, Nav1.2 and Nav1.6, expressed mouse spinal sensory neurons. J Physiol 564, 803–815.
Rush AM & Elliott JR (1997). Phenytoin and carbamazepine – differential inhibition of sodium currents in small cells from adult rat dorsal root ganglia. Neuroscience Lett 226, 95–98.[CrossRef][Medline]
Rush AM & Waxman SG (2004). PGE2 increases the tetrodotoxin-resistant Nav1.9 sodium current in mouse DRG neurons via G-proteins. Brain Res 1023, 264–271.[CrossRef][Medline]
Rush AM, Wittmack EK, Tyrrell L, Black JA, Dib-Hajj SD & Waxman SG (2006b). Differential modulation of sodium channel Nav1.6 by two members of the fibroblast growth factor homologous factor 2 subfamily. Eur J Neurosci 23, 2551–2562.[CrossRef][Medline]
Sangameswaran L, Delgado SG, Fish LM, Koch BD, Jakeman LB, Stewart GR, Sze P, Hunter JC, Eglen RM & Herman RC (1996). Structure and function of a novel voltage-gated, tetrodoxtoxin-resistant sodium channel specific to sensory neurons. J Biol Chem 271, 5953–5956.
Sangameswaran L, Fish LM, Koch BD, Rabert DK, Delgado SG, Ilnicka M, Jakeman LB, Novakovic S, Wong K, Sze P, Tzoumaka E, Stewart GR, Herman RC, Chan H, Eglen RM & Hunter JC (1997). A novel tetrodotoxin-sensitive, voltage-gated sodium channel expressed in rat and human dorsal root ganglia. J Biol Chem 272, 14805–14809.
Shah BS, Rush AM, Liu S, Tyrrell L, Black JA, Dib-Hajj S & Waxman SG (2004). Contactin associates with sodium channel Nav1.3 in native tissues and increases channel density at the cell surface. J Neurosci 24, 7387–7399.
Shah BS, Stevens EB, Gonzalez MI, Bramwell S, Pinnock RD, Lee K & Dixon AK (2000). 3, a novel auxiliary subunit for the voltage-gated sodium channel, is expressed preferentially in sensory neurons and is upregulated in the chronic constriction injury model of neuropathic pain. Eur J Neurosci 12, 3985–3990.[CrossRef][Medline]
Sontheimer H, Fernandez-Marques E, Ullirich N, Pappas CA & Waxman SG (1994). Astrocyte Na+ channels are required for maintenance of Na+/K+-ATPase activity. J Neurosci 14, 2464–2475.[Abstract]
Sontheimer H, Femandez-Marques E, Ullrich N, Pappas CA & Waxman SG (1994). Astrocyte Na+ channels are required for maintenance of Na+/K+-ATPase activity. J Neurosci 14, 2464–2475.[Abstract]
Strassman AM & Raymond SA (1999). Electrophysiological evidence for tetrodotoxin-resistant sodium channels in slowly conducting dural sensory fibers. J Neurophysiol 81, 413–424.
Stucky CL & Lewin GR (1999). Isolectin B4-positive and -negative nociceptors are functionally distinct. J Neurosci 19, 6497–6505.
Stys PK, Sontheimer H, Ransom BR & Waxman SG (1993). Non-inactivating, TTX-sensitive Na+ conductance in rat optic nerve axons. Proc Natl Acad Sci U S A
) is depolarized compared to that of TTX-S currents (
) in DRG neurons. E, the voltage dependence of steady-state inactivation is more depolarized for the TTX-R currents (
80% of knockout Nav1.8–/– mouse small DRG neurons. Full-sized action potentials cannot be recorded in these neurons, which lack Nav1.8 expression. Around 20% of small Nav1.8–/– DRG neurons have a more hyperpolarized RMP that allows overshooting action potentials (Da). Depolarizing the RMP in these neurons (Db, same cell as Da) inactivates the TTX-S channels and demonstrates the importance of Nav1.8 in supporting action potential firing from a depolarized RMP. Adapted from 
