Modification of sodium channel gating in frog myelinated nerve fibres by Centruroides sculpturatus scorpion venom.

1. The effect of Centruroides sculpturatus scorpion venom on single frog myelinated nerve fibres was studied. Sodium currents through the nodal membrane were measured under voltage-clamp conditions before and after exposure to venom in Ringer solution 1-5 mug/ml. for 1-3 min. 2. Centruroides venom brings about repetitive firing and increased membrane potential noise. Spontaneous firing was also observed. Eventually the nodal membrane becomes inexcitable following venom treatment. 3. Under voltage clamp with a step depolarization of the membrane potential, activation and inactivation of sodium currents turns on, reaches a peak within about 25 msec, and then declines over several hundred milliseconds. As the amplitude and duration of the depolarizing pulse are increased, the size of the venom-induced current that follows also increases. 4. The venom-induced current turns on exponentially with a time constant near the value of the time constant for recovery from inactivation, tau-h, at the resting membrane potential. A depolarizing pulse inactivates this new current component, while a hyperpolarizing pulse leads to a larger venom-induced current immediately after the hyperpolarization. Its time course and membrane potential dependence indicate that the venom-induced current is modulated by the sodium inactivation process. 5. The membrane potential dependence of sodium activation in some channels is shifted by 40-50 mV in the hyperpolarizing direction. Depolarization increases the proportion of channels with shifted activation gating by first-older kinetics. Following a depolarizing pulse the activation parameter, m-3, remains elevated for hundreds of milliseconds, allowing channels to reopen as recovery from inactivation occurs. 6. A kinetic model with normal inactivation gating and shifted activation gating in some channels accounts for the observed voltage-clamp currents and for the repetitive firing evoked by Centruroides venom. In the model normal channels are converted to channels with shifted activation gating by a voltage dependent reaction. 7. The results suggest limits to possible coupling between sodium channel activation and inactivation. Transitions of the inactivation parameter, h, can occur normally in channels with a shifted membrane potential dependence for activation.