Voltage and temperature dependence of normal and chemically modified inactivation of sodium channels. Quantitative description by a cyclic three-state model.

(1) Voltage clamp experiments were done on single myelinated nerve fibres of the frog, Rana esculenta, with 10 mM TEA in the external solution to block potassium channels. (2) The potential dependence of normal sodium current inactivation was studied over a potential range of V = -50 mV to 80 mV. At depolarizations (V greater than or equal to 30 mV) inactivation is diphasic. The relative contribution of the fast phase increases from 0.4 at V = 30 mV to 0.96 at V = 80 mV. At resting potential (V = 0 mV) recovery from inactivation shows a sigmoidal time course. At strong hyperpolarization (V = -50 mV) recovery is diphasic with a predominant fast phase. (3) For a quantitative description of these findings a cyclic three-state model of inactivation, with one open and two closed states, is formulated. The potential dependence of the rate constants is determined and calculations from this model are compared with the experimental data. (4) To test the availability of the proposed model, normal inactivation was modified by treatment with 0.6 mM chloramine-T. This substance causes inactivation to become slow and incomplete; the potential dependence of steady-state inactivation becomes non-monotonic. All these effects are explained as quantitative changes of the rate constants in the cyclic inactivation model. (5) The influence of temperature on normal inactivation was studied at a range of 8-20 C. Both time constants as well as the two inactivation components are temperature-dependent. For a quantitative description of temperature effects by the cyclic model, the activation enthalpies of the rate constants are evaluated.(ABSTRACT TRUNCATED AT 250 WORDS)