Activation of the action potential Na+ ionophore by neurotoxins. An allosteric model.

The alkaloid neurotoxins aconitine, veratridine, grayanotoxin, and batrachotoxin activate the action potential Na+ ionophore by interaction with a common binding site. Concentration-response curves are fit by simple Langmuir isotherms. The fraction of Na+ ionophores activated at saturating concentrations of neurotoxin are: aconitine, 0.02; veratridine, 0.08; grayanotoxin, 0.51; and batrachotoxin, 0.95. The concentrations required to obtain 50% of the maximum activation are: aconitine, 3.6 x 10m6 M; veratridine, 2.9 X 10ms M; grayanotoxin, 1.2 x 1O-3 M; and batrachotoxin, 7.0 X It7 M. Incubation of cells with scorpion toxin causes an increase in the fraction of Na+ ionophores activated at saturating concentrations of alkaloid toxins (P,) and a decrease in the concentration required to obtain 50% of maximum activation (K,,,): aconitine, P, = 0.21, Ko.5 = 2.7 x 10m6 M; veratridine, P, = 0.56, Ko.s = 1.5 x 1O-5 M; grayanotoxin, P, = 0.96, K,,, = 9.2 x 10m5 M; batrachotoxin, P, = 1.0, K,., = 5.2 x 10-S M. For the partial activators, the primary effect of scorpion toxin is to increase P,. For the full activators, the primary effect of scorpion toxin is to decrease K,,.5. In each case the concentration response curves are fit by a simple Langmuir isotherm with a Hill coefficient of 1.0. An allosteric mode1 is presented which describes the activation of the Na+ ionophore by alkaloid toxins and the heterotropic cooperative effect of scorpion toxin. In this model, the Na+ ionophore is assumed to exist in two states, active and inactive. Alkaloid toxins activate the ionophore by binding preferentially to the active state. Scorpion toxin enhances activation by alkaloid toxins by altering the equilibrium constant (allosteric constant) for the transition between the active and inactive states.