Molecular dissection of the myelinated axon.
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.
Waxman
S G
SG
Department of Neurology, Yale University School of Medicine, New Haven, CT.
Ritchie
J M
JM
D000818:Animals; D001253:Astrocytes / Q000648:ultrastructure; D001369:Axons / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D004594:Electrophysiology; D006801:Humans; D007473:Ion Channels / Q000378:metabolism / Q000502:physiology; D009186:Myelin Sheath / Q000378:metabolism*; D009422:Nervous System Diseases / Q000188:drug therapy; D009431:Neural Conduction; D011901:Ranvier's Nodes / Q000648:ultrastructure; D012583:Schwann Cells / Q000648:ultrastructure; D019831:Sodium-Calcium Exchanger; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D002352:Carrier Proteins; D007473:Ion Channels; D019831:Sodium-Calcium Exchanger; D000252:Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase