Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons - PubMed (original) (raw)

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Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons

Anthony M Rush et al. J Physiol. 2007.

Abstract

Dorsal root ganglion neurons express an array of sodium channel isoforms allowing precise control of excitability. An increasing body of literature indicates that regulation of firing behaviour in these cells is linked to their patterns of expression of specific sodium channel isoforms, which have been discovered to possess distinct biophysical characteristics. The pattern of expression of sodium channels differs in different subclasses of DRG neurons and is not fixed but, on the contrary, changes in response to a variety of disease insults. Moreover, modulation of channels by their environment has been found to play an important role in the response of these neurons to stimuli. In this review we illustrate how excitability can be finely tuned to provide contrasting firing templates in different subclasses of DRG neurons by selective deployment of various sodium channel isoforms, by plasticity of expression of these proteins, and by interactions of these sodium channel isoforms with each other and with other modulatory molecules.

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Figures

Figure 1

Figure 1. TTX-R currents carried by Nav1.8 have more depolarized voltage dependence than TTX-S currents in DRG neurons

Total sodium current in this DRG cell elicited using a holding potential of −100 mV and 25 ms step depolarizations to voltages ranging from −80 to +40 mV (A) can be pharmacologically separated on the basis of sensitivity to TTX (100 n

m

), allowing isolation of TTX-R currents (B) and by subtracting B from A, TTX-S currents (C). D, the voltage dependence of activation for TTX-R currents (▪) 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 (▪) than for TTX-S currents (○). The voltage dependence of inactivation was estimated by measuring currents elicited by 20 ms test pulses to −10 mV after 500 ms inactivating prepulses ranging from −130 to −10 mV. Adapted from data in Cummins & Waxman (1997) with permission; ©1997 by the Society for Neuroscience.

Figure 2

Figure 2. The TTX-R Nav1.8 channel is a major contributor to the action potential upstroke in small DRG neurons

A, TTX-R single action potentials recorded from small DRG neurons from a Nav1.8+/+ mouse, in the presence of 250 n

m

TTX. B, a longer injection of current for 1 s generates a train of TTX-R action potentials in the same neuron. C, recordings under similar conditions as in (A), but in the absence of TTX, demonstrate that only graded potentials can be elicited from ∼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 Renganathan et al. (2001) with permission; © 2001 The American Physiology Society.

Figure 3

Figure 3. Nav1.8 supports repetitive firing in small DRG neurons in response to sustained depolarization

Long injections of current for 1 s (C) generate a train of action potentials in Nav1.8+/+ small DRG neurons (A). The depolarized steady-state properties and rapid recovery from inactivation of the Nav1.8 channel permit this firing despite a relatively depolarized RMP. In contrast, Nav1.8−/− neurons are incapable of sustaining high frequency firing in response to identical stimuli (B). Adapted from Renganathan et al. (2001) with permission; © 2001 The American Physiology Society.

Figure 4

Figure 4. A rapidly repriming TTX-S sodium current, largely attributable to Nav1.3 channels, emerges in DRG neurons following transection of their peripheral axons

A, family of TTX-S sodium current recordings from intact DRG neuron, showing recovery from inactivation at −80 mV. B, family of TTX-S sodium currents from a similar neuron 7 days after peripheral axotomy, demonstrating accelerated recovery from inactivation. C, single exponential fits showing accelerated repriming following peripheral axotomy. Modified from Black et al. (1999) with permission; © 2001 The American Physiology Society.

Figure 5

Figure 5. Putative roles of different sodium channel subtypes in electrogenesis in small DRG neurons

Representation of subthreshold responses and overshooting action potentials are shown from small intact and axotomized DRG neurons. Under normal conditions, Nav1.7 (and Nav1.9 in some cells) is likely to bring the neuron towards threshold, and Nav1.8 is largely responsible for the overshooting action potential. Note the large depolarization necessary for action potential generation, due to the depolarized voltage dependence of activation of Nav1.8. In contrast, axotomized DRG neurons are likely to have a more hyperpolarized threshold for overshooting action potential, in line with the predominance of TTX-S (Nav1.1, Nav1.3 and Nav1.6) channels requiring less depolarization for activation and the boosted ramp currents with the presence of Nav1.3. Note that Nav1.8 and Nav1.9 are no longer involved due to down-regulation of expression after axotomy.

Figure 6

Figure 6. Distinct biophysical characteristics of the Nav1.7 sodium channel shape its role in DRG neurons

Trains of 50 Hz stimulation show that sodium channel Nav1.7 is unable to follow and sustain high frequency firing (B), when compared to, for example, Nav1.4 (A). Thus Nav1.7 is unlikely to play a major role in the action potential upstroke during repetitive firing. Using ramp stimulation to mimic small graded subthreshold potentials, Nav1.4 produces only a small response (C), in marked contrast to the large ramp current evoked with Nav1.7 (D), similar to those that can be recorded from small DRG neurons (E) (the asterisk marks a second component, blocked by cadmium and therefore likely to be due to calcium influx). F, Nav1.7 has much slower onset of inactivation than Nav1.4. Because of this, small changes in membrane potential, such as generator potentials, produce less closed-state inactivation in Nav1.7. Resistance to this form of inactivation enables Nav1.7 to respond to small, slow depolarizations close to RMP, boosting these depolarizations and bringing the cell closer to action potential threshold. Adapted from Cummins et al. (1998) with permission; ©1998 by the Society for Neuroscience.

Figure 7

Figure 7. The erythromelalgia Nav1.7 mutation L858H inhibits firing in SCG neurons, which can be rescued by coexpression of Nav1.8 channels

When Nav1.8 is coexpressed with the Nav1.7 mutant L858H, current threshold and action potential overshoot are restored, even though the depolarization of RMP induced by L858H persists. A, suprathreshold action potentials recorded from representative superior cervical ganglion (SCG) neurons transfected with WT (blue), L858H (red) and L858H plus Nav1.8 (green) channels. B, depolarized RMP in cells with L858H channels is maintained with coexpression of Nav1.8 (P > 0.05). Dashed line indicates RMP in cells expressing WT Nav1.7 alone. C, current threshold for action potential firing is reduced by L858H coexpression with Nav1.8, when compared to L858H alone (P < 0.05). D, action potential overshoot in SCG neurons with L858H channel is increased when Nav1.8 is coexpressed with L858H (41.5 ± 4.6 mV, n = 17; P < 0.05). Thus, the introduction of Nav1.8, with depolarized activation and inactivation characteristics, allows SCG neurons to fire full overshooting action potentials, despite the depolarization induced by the L858H erythromelalgia mutation in Nav1.7. Adapted from Rush et al. (2006_a_) with permission; © 2006 National Academy of Sciences, USA.

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