NONINACTIVATING, TETRODOTOXIN-SENSITIVE NA-NERVE AXONS( CONDUCTANCE IN RAT OPTIC)

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.