A NO and Sodium Channels

Sodium channels are perhaps the single-most important ion channel in axons (see Chapter 7, this volume), so it is sig nificant that many reports describe potent effects of NO on sodium channel physiology. No single effect of NO emerges from the different reports, and this likely reflects the use in the different studies of different concentrations of NO (some of which may be supra-pathophysiological) and the examination of different NO species, studied in different ways on different subtypes of channel within different cell types (where different accessory proteins/factors may be present). It is also clear, however, that sodium channel properties are modified in whole cell preparations by the relatively low concentrations of NO produced by the cells themselves. Both cGMP-mediated (e.g. Smith and Otis, 2003) and cGMP-independent (e.g., thiol modification; Renganathan et al., 2002b; Ahern et al., 2000) actions of NO on sodium channels have been reported.

NO can both substantially potentiate the persistent sodium current (Ahern et al., 2000), or block both this current and the fast and slow sodium currents (Li et al., 1998; Renganathan et al., 2000, 2002a, 2002b; Bielefeldt et al., 1999). The persistent sodium current is normally a small fraction (~1%) of the transient sodium current associated with the formation of an action potential, but because it is persistent, it can significantly affect the physiological properties of axons by biasing axonal excitability. In one study, bath application of NO to pituitary nerve terminals increased the channel activity in excised outside-out patches from almost nothing >20 ms after the start of a depolarizing pulse, to high activity throughout the duration of a 50 ms pulse (Fig. 4) (Ahern et al., 2000). Similar findings regarding the persistent current, with little effect on the transient current, have also been reported in excised patches from hippocampal neurons (Hammarstrom and Gage, 1999) (see also Sawada et al., 1995).

In another preparation (cardiac myocytes), an increase in persistent sodium current resulted from ionomycin treatment to stimulate the endogenous production of NO (Ahern et al., 2000). Thus even relatively low concentrations of NO can produce an increase in channel open probability. Such changes would be expected to increase axonal excitability, and it is interesting to speculate on whether the changes may contribute to the hyperexcitabil-ity expressed by demyelinated axons (Smith et al., 1997; Baker, 2000). Indeed, there is evidence that the generation of ectopic impulses at sites of demyelination along central axons can be due to a persistent sodium current that develops at these sites (Rizzo et al., 1996b; Kapoor et al., 1997; Smith et al., 1997; Baker, 2000; Baker and Bostock, 1992; see Chapter 9). The potential effects of NO on axons may be expected to be diversified in MS because of the appearance along some demyelinated axons of atypical sodium channels for the site of expression. Thus although the dominant subtype of sodium channels at nodes of Ranvier in the adult is Nav1.6, there is a switch to include Nav1.2 along some demyelinated axons in animals with EAE

Figure 4 Records showing the effect of NO applied to myocytes on the flash photolysis of sodium nitroprusside. Note that the persistent sodium current following the spike (which goes off scale) is increased many fold. The increase was reversed by the sulphydryl alkylating agent N-ethylmaleimide (NEM). (Reproduced from Ahern et al., 2000.)

Figure 4 Records showing the effect of NO applied to myocytes on the flash photolysis of sodium nitroprusside. Note that the persistent sodium current following the spike (which goes off scale) is increased many fold. The increase was reversed by the sulphydryl alkylating agent N-ethylmaleimide (NEM). (Reproduced from Ahern et al., 2000.)

(Craner et al., 2003) and patients with MS (Craner et al., 2004b).

Unmyelinated axons from dorsal root ganglion cells enter the spinal cord and also, therefore, are affected by spinal inflammatory lesions in MS. Sodium channels in the neurons of such axons are prominently affected by NO, and NO donors block the fast, slow, and persistent sodium currents of such neurons by S-nitrosation (Renganathan et al., 2002b). Indeed, there is evidence that NO can act as an autocrine regulator of sodium currents in these cells (Renganathan et al., 2000).

Unsurprisingly, given its wide range of effects, exposure to NO can change the electrophysiological properties of whole neurons, and it has been found to excite or inhibit spontaneous firing in different neurons when applied to the whole spinal cord (Pehl and Schmid, 1997). Sustained (> 40 minute) increases in the spontaneous firing rate of Purkinje neurons has been observed in response to activation of the NO-cGMP signaling pathway using NO donors (Smith and Otis, 2003). Similar effects can result from NO generated by parallel fiber activity (Smith and Otis, 2003).

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