Noninactivating, tetrodotoxin-sensitive Na+ conductance in rat optic nerve axons.
The ionic current underlying the upstroke of axonal action potentials is carried by rapidly activating, voltage-dependent Na+ channels. Termination of the action potential is mediated in part by the rapid inactivation of these Na+ channels. We previously demonstrated that an influx of Na+ plays a critical role in the cascade leading to irreversible anoxic injury in central nervous system white matter. We speculated that a noninactivating Na+ conductance mediates this pathological Na+ influx and persists at depolarized membrane potentials as seen in anoxic axons. In the present study we measured the resting compound membrane potential of rat optic nerves using a modified "grease-gap" technique. Application of tetrodotoxin (2 microM) to resting nerves ([K+]o = 3 mM) or to nerves depolarized by 15 or 40 mM K+ resulted in hyperpolarizing shifts of membrane potential. We interpret these shifts as evidence for a persistent, noninactivating Na+ conductance. This conductance is present at rest and persists in nerves depolarized sufficiently to abolish classical transient Na+ currents. PK/PNa ratios were estimated at 35.5, 23.2, and 88 in 3 mM, 15 mM, and 40 mM K+, respectively. We suggest that this noninactivating Na+ conductance may provide an inward pathway for Na+ ions, necessary for the operation of Na+, K(+)-ATPase. Under pathological conditions, such as anoxia, this conductance is the likely route of Na+ influx, which causes damaging Ca2+ entry through reverse operation of the Na(+)-Ca2+ exchanger. The presence of this conductance in white matter axons may provide a therapeutic opportunity for diseases such as stroke and spinal cord injury.
Stys
P K
PK
Department of Neurology, Yale School of Medicine, New Haven, CT 06510.
Sontheimer
H
H
Ransom
B R
BR
Waxman
S G
SG
D000818:Animals; D004553:Electric Conductivity; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009900:Optic Nerve / Q000502:physiology*; D051381:Rats; D012964:Sodium / Q000502:physiology*; D015222:Sodium Channels / Q000187:drug effects*; D013779:Tetrodotoxin / Q000494:pharmacology*
D015222:Sodium Channels; D013779:Tetrodotoxin; D012964:Sodium