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/mum2) in the nodal axon membrane and are present at lower density (< 25/mum2) 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 hyper-polarization. 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) Ca2+-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.
