Pk. Stys et al., NONINACTIVATING, TETRODOTOXIN-SENSITIVE NA-NERVE AXONS( CONDUCTANCE IN RAT OPTIC), Proceedings of the National Academy of Sciences of the United Statesof America, 90(15), 1993, pp. 6976-6980
The ionic current underlying the upstroke of axonal action potentials
is carried by rapidly activating, voltage-dependent Na+ channels. Term
ination of the action potential is mediated in part by the rapid inact
ivation of these Na+ channels. We previously demonstrated that an infl
ux of Na+ plays a critical role in the cascade leading to irreversible
anoxic injury in central nervous system white matter. We speculated t
hat a noninactivating Na+ conductance mediates this pathological Na+ i
nflux and persists at depolarized membrane potentials as seen in anoxi
c axons. In the present study we measured the resting compound membran
e potential of rat optic nerves using a modified ''grease-gap'' techni
que. Application of tetrodotoxin (2 muM) to resting nerves (K+!o = 3
mM) or to nerves depolarized by 15 or 40 mM K+ resulted in hyperpolari
zing shifts of membrane potential. We interpret these shifts as eviden
ce for a persistent, noninactivating Na+ conductance. This conductance
is present at rest and persists in nerves depolarized sufficiently to
abolish classical transient Na+ currents. P(K)/P(Na) ratios were esti
mated 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+-ATP
ase. Under pathological conditions, such as anoxia, this conductance i
s the likely route of Na+ influx, which causes damaging Ca2+ entry thr
ough reverse operation of the Na+-Ca2+ exchanger. The presence of this
conductance in white matter axons may provide a therapeutic opportuni
ty for diseases such as stroke and spinal cord injury.