Distribution of Ion Channels in Myelinated Axons

Experiments involving isolated nodal voltage-clamping, isolated internodal voltage-clamping (following the acute removal of myelin by detergents such as lysolethicin), patch-clamping demyelinated axons, recordings of electro-tonus from normal axons and immunocytochemistry of peripheral and central axons have elucidated and confirmed the normal distribution of ion channel types in myelinated nerve (Chiu et al., 1979; Baker et al., 1987; Roper and Schwarz, 1989; Reid et al., 1999; Rasband and Shrager, 2000). The patterns in the peripheral nervous system (PNS) and CNS appear similar. Normally, transiently opening Na+ channels are confined to the nodes of Ranvier, and are present at densities of around 2,000 per |im2 (estimated from nonstationary noise analysis, gating current measurements, and by counting freeze-fracture particles, reviewed by Ritchie, 1995). A far lower density of several tens of channels per | m2 is thought to be present in the internode (Chiu and Schwarz, 1987), insufficient to confer excitability on the internodal membrane (although in absolute terms the node and internode may have similar numbers of channels, as the internodal membrane area is three orders of magnitude larger than that of a node). The normal peripheral axon also has kinetically fast and slow delayed rectifier K+ channels (GKf and GKs, respectively), corresponding well with the fast and slow K+ current kinetics originally described in frog axons by J.-M. Dubois (Dubois, 1981). The fast and slow K+ channels in the mammal exhibit a complementary distribution. The fast channels are present at the juxtapara-nodal regions under the myelin (Ritchie and Chiu, 1981; Roper and Schwarz, 1989; Rasband and Shrager, 2000), whereas the slow K+ channels contribute to nodal conductance (Baker et al., 1987; Roper and Schwarz, 1989) activating during a train of action potentials, and providing a major component of axonal accommodation. In normal adult mammalian axons, the contribution of fast K+ channels to nodal repolarization after an action potential is minimal (Chiu et al., 1979). Repolarization after an action potential takes place by way of a circuit incorporating the relatively vast internodal capacity (Barrett and Barrett, 1982, and Baker et al., 1987; reviewed by Baker, 2000a). Any loosening or retraction of myelin thus exposes kinetically fast K+ channels, which will stabilize the nodal membrane potential, potentially compromising conduction. The normal distribution of conductances with Na+ channels at the nodes and fast K+ channels under the myelin is summarized in Fig. 1.

During the few days after diphtheritic demyelination (e.g., 5 to 7 days), the electrophysiological properties of

Figure 1 Simplified distribution of Na+ and K+ conductances in a myelinated axon. In the normal axon (upper distribution), the node possesses a Na+ conductance (GNa) and kinetically slow K+ channels (GKs). The highest density of both these channel types is found at the node of Ranvier. Kinetically fast K+ channels (GKf) have their highest density under the myelin in a band at the juxtaparanodal region (shading). There is a much lower density of Na+ channels and slow K+ channels in the internodal membrane (GNa, GKs). After segmental demyelination, the original node becomes a heminode and a Na+ channel distribution is established with a higher than normal density of channels in the exposed internodal membrane. This is indicated by a movement of Na+ channels away from the node. In addition, the punctate distribution of fast K+ channels breaks down, and they are distributed away from the juxtaparanode, indicated by a movement into the node and internode.

Figure 1 Simplified distribution of Na+ and K+ conductances in a myelinated axon. In the normal axon (upper distribution), the node possesses a Na+ conductance (GNa) and kinetically slow K+ channels (GKs). The highest density of both these channel types is found at the node of Ranvier. Kinetically fast K+ channels (GKf) have their highest density under the myelin in a band at the juxtaparanodal region (shading). There is a much lower density of Na+ channels and slow K+ channels in the internodal membrane (GNa, GKs). After segmental demyelination, the original node becomes a heminode and a Na+ channel distribution is established with a higher than normal density of channels in the exposed internodal membrane. This is indicated by a movement of Na+ channels away from the node. In addition, the punctate distribution of fast K+ channels breaks down, and they are distributed away from the juxtaparanode, indicated by a movement into the node and internode.

axons can be substantially altered by a redistribution of Na+ and K+ channels. Impulse conduction can be restored by an increase in the number of Na+ channels expressed in the normally electrically unexcitable internode (Bostock and Sears, 1978), allowing continuous conduction and thus the restoration of function (Fig. 1), albeit with prolonged conduction times. The same authors (Sherratt et al., 1980; Bostock et al., 1981) also showed that blockade of axonal fast K+ channels exposed by myelin withdrawal, using the channel blocker 4-aminopyridine, could help overcome conduction failure after demyelination. This provided a clinical strategy for the symptomatic treatment of MS that has met with some success (e.g., Schwid et al., 1997, and Sheean et al., 1998), although it is limited by the nonspecific effects of K+ channel blockers on nervous system function. Craner et al. (2003) reported that in allergic encephalomyelitis, apparently demyelinated optic nerve axons express NaV1.6 and NaV1.2, the channels being present diffusely and continuously over many tens of microns. These Na+ channel subtypes are therefore likely to contribute to the conferment of excitability on internodal membrane. In demyelinated lesions of rat sciatic nerve, Rasband et al. (1998) described a redistribution of kinetically fast K+ channels (KV1.1 and KV1.2) away from the normal juxtaparanodal sites to a more diffuse distribution, including nodes. Moreover, some damaged axons were devoid of immunostaining for fast K+ channels, a situation that could potentially encourage ectopic activity. These authors also reported that with remyelination, the K+ channel distribution was only partially restored. After spinal cord injury that included demyelination, the punctuate distribution of KV1.1 in central axons was lost, and a more diffuse distribution of channels became evident (Nashmi et al., 2000). Thus, although conduction may be restored by the remodeling of axonal membrane properties after demyelination, axons can become ectopic impulse generators, and the clinical use of K+ channel blocking agents would be expected to make this more likely.

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