Roles of Ca Channels in Demyelinating Diseases

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Since axonal degeneration is now recognized to be a prominent feature in demyelinating diseases, Ca channels might be pathologically relevant if they predispose axons to Ca-mediated damage. There are three mechanisms by which axonal Ca influx can be modulated in demyelination: unmasking of existing Ca channels in the internode, changes in gene expression of other ion channels, and changes in gene expression of Ca channels.

1. Increased Ca Influx per Unit Length by Unmasking Ca Channels on the Internode

The diffuse staining pattern for L-type Ca channels in a mature optic nerve suggests that the channels are normally masked by the myelin (Brown et al., 2001). Demyelination will markedly increase activity-dependent Ca influx per unit axon length by unmasking these existing internodal Ca channels, potentially contributing to excitotoxcity. It is possible that Ca clearance will also be compromised in demyelinated axons if they accumulate excessive Na. Na accumulation during repetitive activity has been shown to inhibit Ca clearance (Verbny et al., 2002), possibly by retardation of Ca extrusion via the Na/Ca exchanger. Figure 7A shows superimposed traces of axonal Ca elevation in a neonatal optic nerve evoked by a single and a train of 20 action potentials. Axonal Ca rises and then falls after cessation of the action

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Before

After nicotine

Before

After nicotine

Figure 6 Calcium-permeable, nicotinic acetylcholine receptors on axons of neonatal mouse optic nerves. Axons were loaded with calcium indicators according to Fig. 4A, and pseudo-color calcium images of axons were monitored before (A) and after (B) 50 |M nicotine was bath applied. (C, D) Computed AF/F from images in A and B, showing the percent calcium change on a pixel-by-pixel basis. Bar is 5 | m. (Reproduced from Zhang et al., 2004, with permission.)

Before

After nicotine

Figure 7 Coupling of calcium clearance to Na accumulation in axons of repetitively stimulated neonatal mouse optic nerves. (A) Axonal calcium fluorescence during a single and a train of 20 action potentials. (B) Normalized time course of the return of axonal calcium to the resting level following the action potentials. Note that return (i.e., calcium clearance) is slower after the 20 action potential train. (C) Increasing axonal Na with the Na-ionophore monensin retards the calcium clearance following action potentials. These studies suggest that activity-dependent Na accumulation in axons retards calcium clearance following repetitive action potentials. (Reproduced from Verbny et al., 2002, with permission.)

Figure 7 Coupling of calcium clearance to Na accumulation in axons of repetitively stimulated neonatal mouse optic nerves. (A) Axonal calcium fluorescence during a single and a train of 20 action potentials. (B) Normalized time course of the return of axonal calcium to the resting level following the action potentials. Note that return (i.e., calcium clearance) is slower after the 20 action potential train. (C) Increasing axonal Na with the Na-ionophore monensin retards the calcium clearance following action potentials. These studies suggest that activity-dependent Na accumulation in axons retards calcium clearance following repetitive action potentials. (Reproduced from Verbny et al., 2002, with permission.)

potentials. The restoration of Ca to the resting level is slower after more action potentials (Fig. 7B). This slow Ca clearance appears to be coupled to Na loading during the repetitive nerve activity, as artificially increasing axonal Na with an ionophore (monensin) also retards post-tetanus Ca clearance (Fig. 7C). Na-loading in metabolically compromised demyelinated axons will exacerbate the effect of unmasked Ca influx by retarding Ca clearance. Finally, L-type Ca channels are coupled to ryanodine receptors in clusters, and these clusters have been suggested to mediate a toxic level of Ca release from intracellular stores in ischemic axons (Quardouz et al., 2003). Whether the unmasking of L-type channels/ryanodine clusters in demyelination contributes to excitotoxcity remains to be examined.

2. Modulation of Axonal Ca Loading via Changes in Gene Expression of Other Ion Channels

Changes in gene expression of Na and K channels in demyelination could modulate Ca influx in demyelination axons. For example, upregulation of Na channels seen in some demyelinating lesions might augment Ca influx by virtue of Ca permeation through Na channels. Further, increasing Na channel expression might result in higher activity-dependent Na accumulation, thereby augmenting Ca loading via retardation of Ca extrusion (Verbny et al., 2002). Changes in K channel expression in demyelination also can indirectly regulate activity-dependent Ca influx. In general, overexpression of K channels in demyelinating diseases should be neuroprotective (by limiting activation of voltage-gated Ca channels), whereas downregulation of K channels should be pathological (by exacerbating Ca channel activation via prolonged membrane depolarization). Highly specific K channel toxins are now available to identify K channel subtypes important in modulating activity-dependent Ca influx in axons. For example, in mouse postganglionic sympathetic axon bundles, blocking Kv1.2 augments activity-dependent Ca transient (Jackson et al., 2001). Upregulation of Kv1.1/Kv1.2 in the CNS fiber tracts of the dysmyelinating mutant Shiverer mice might be neuroprotective against calcium-mediated damage (Wang et al., 1995).

3. Upregulation of Calcium Channels in Demyelination

Besides unmasking existing Ca channels, demyelination also can increase axonal Ca influx if there is an unregulation of Ca channels. Kornek and co-workers (Kornek et al., 2001) observed that N-type Ca channel immunoreactivity is nondetectable in normal adult myelinated nerves, but upregulated in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) model of demyelination. The N-type Ca channel proteins are ectopically expressed in actively demyelinating lesion sites, and the pore-forming subunit appears to be inserted onto the axolemma (Kornek et al., 2001). This article is important, because it shows for the first time that certain axonal Ca channel subtypes are upregulated in multiple sclerosis, leading to the suggestion that expression of Ca channels might contribute to axonal degeneration in inflammatory demyelinating disorders (Kornek et al., 2001). An important issue is whether the Ca channel proteins observed in the study of Kornek et al. (2001) are functional and mediate Ca influx. We have addressed this issue by measuring activity-dependent Ca transients in hypomyelinated PNS axons from the Po-over-expressor mice. Activity-dependent Ca transients are absent in normal axons, but strongly present in hypomyeli-nated axons, suggesting that Ca channels expressed in hypomyelinated axons are functional. Whether these Ca transients contribute to axonal degeneration in these nerves remains to be explored.

Besides voltage-gated Ca channels, ligand-gated Ca channels also might contribute to Ca-mediated axonal injury. In the mammalian optic nerves, nicotine-induced axonal Ca elevation declines as the nerve matures, suggesting a downregulation or masking of nAChR by the myelin sheath (Zhang et al., 2004). Of interest, nAChR-mediated Ca response is present in hypomyelinated axons of the Jimpy optic nerves, suggesting either an upregula-tion of nAChR or an unmasking of existing nAChR during demyelination. Thus, both voltage-gated and ligand-gated Ca channels are operative in demyelinated axons and potentially contribute to Ca-mediated axonal degeneration.

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