Molecular dissection of the myelinated axon

Abstract

The membrane of the myelinated axon expresses a rich repertoire of physiologically active molecules: (1) Voltage-sensitive NA+ channels are clustered at high density (approximately 1,000/microns 2) in the nodal axon membrane and are present at lower density (< 25/microns 2) in the internodal axon membrane under the myelin. Na+ channels are also present within Schwann cell processes (in peripheral nerve) and perinodal astrocyte processes (in the central nervous system) which contact the Na+ channel-rich axon membrane at the node. In some demyelinated fibers, the bared (formerly internodal) axon membrane reorganizes and expresses a higher-than-normal Na+ channel density, providing a basis for restoration of conduction. The presence of glial cell processes, adjacent to foci of Na+ channels in immature and demyelinated axons, suggests that glial cells participate in the clustering of Na+ channels in the axon membrane. (2) "Fast" K+ channels, sensitive to 4-aminopyridine, are present in the paranodal or internodal axon membrane under the myelin; these channels may function to prevent reexcitation following action potentials, or participate in the generation of an internodal resting potential. (3) "Slow" K+ channels, sensitive to tetraethylammonium, are present in the nodal axon membrane and, in lower densities, in the internodal axon membrane; their activation produces a hyperpolarizing afterpotential which modulates repetitive firing. (4) The "inward rectifier" is activated by hyperpolarization. This channel is permeable to both Na+ and K+ ions and may modulate axonal excitability or participate in ionic reuptake following activity. (5) Na+/K(+)-ATPase and (6) Ca(2+)-ATPase are also present in the axon membrane and function to maintain transmembrane gradients of Na+, K+, and Ca2+. (7) A specialized antiporter molecule, the Na+/Ca2+ exchanger, is present in myelinated axons within central nervous system white matter. Following anoxia, the Na+/Ca2+ exchanger mediates an influx of Ca2+ which damages the axon. The molecular organization of the myelinated axon has important pathophysiological implications. Blockade of fast K+ channels and Na+/K(+)-ATPase improves action potential conduction in some demyelinated axons, and block of the Na+/Ca2+ exchanger protects white matter axons from anoxic injury. Modification of ion channels, pumps, and exchangers in myelinated fibers may thus provide an important therapeutic approach for a number of neurological disorders.

Conduction in Segmentally Demyelinated Mammalian Central Axons

“…The lesions are often several millimeters long, and so the axons must lose one or more internodes of myelin, i.e., they are often segmentally demyelinated. In experimental lesions, the onset of segmental demyelination is seemingly routinely accompanied by conduction block (attributable to an initial paucity of sodium channels along the newly exposed axolemma) (for review, see Waxman and Ritchie (1993), but the lesion in MS can sometimes become, or remain, asymptomatic (Ghatak et al, 1974;Phadke and Best, 1983). In some cases the asymptomatic nature of the lesion can be explained by its location in a clinically silent area of the brain, or in a location where f unction can be subserved by an alternative pathway, but these possibilities cannot always explain the presence of continued f unction.…”

Potassium channel blockers as an effective treatment to restore impulse conduction in injured axons

“…This system enhances electrical impulse transmission, as depolarization jumps from node to node in a process called saltatory conduction. Because the action potentials are only generated at the node of Ranvier, conduction through this system is faster and much more efficient than conduction through unmyelinated axons [2,11,12] .…”

“…Saltatory conduction relies on both myelin encasement and the asymmetric distribution of ionic channels [2,11,12] . Compared to the internodal region, the node of Ranvier has a significantly higher density of sodium channels, which enables the generation of action potential at the node.…”

“…Specifically, when the node membrane is adequately depolarized by incoming current, voltage-dependent sodium channels will open, allowing sodium influx and initiating the action potential. Potassium channels reside at a high density beneath the myelin at the juxtaparanodel area, separated from the node by the paranodal region [2,11,12] . Although the functions of these potassium channels in normal healthy axons remain entirely unclear, these channels are thought to be involved in stabilizing the axonal membrane potential [13][14][15][16] .…”

Intra-axonal recording from large sensory myelinated axons: Demonstration of impaired membrane conductances in early experimental diabetes

“…Fast sodium channels located almost exclusively on nodal membrane are modulated by fast and slow outwardly rectifying potassium conductances located in the internodal membrane [11,13,15]. In addition, inward rectification induced by membrane hyperpolarization has also been shown in axons of the mammalian [16,17,18,19] and amphibian [20] peripheral nervous system.…”