Relations between the inactivation of sodium channels and the immobilization of gating charge in frog myelinated nerve

Publisher Website
Google Scholar
Abstract
Single, voltage-clamped nerve fibers of Rana esculenta were stimulated with P/2 pulse patterns for measuring Na and gating currents at 13.degree. C. Gating currents during test pulses to -122 or +10 mV were measured after 45 ms conditioning steps to voltages between -122 and -18 mV. As the conditioning voltage was made more positive than -80 mV, the movable gating charge diminished along a sigmoid curve, approaching a value of nearly 1/3 of the maximum charge. Na inactivation began at a more negative potential and proceeded to undetectable levels. After a depolarizing prepulse, both time constant and size of the charge movement depended less steeply on the test voltage than normally. The prepulse reduced gating currents associated with steps from -122 to test voltages .gtoreq. -40 mV, but enhanced gating currents obtained with test voltages < -40 mV. Increasing the duration of a depolarizing pulse (-54 to +42 mV) reduced the fast off gating current at the end of the pulse and enhanced a slow component. Their total charge corresponded approximately to that carried during the pulse. During depolarization, Na current inactivated in a fast and a slow phase. The fast phase was also reflected in the loss of fast charge movement (immobilization) as seen after the pulse was interrupted at various durations. The available Na current and the fast movement of gating charge diminished in parallel during prepulses more positive than -54 mV, and recovered in parallel upon repolarization to levels between -102 and -46 mV. During prepulses between -62 and -78 mV, Na inactivation occurred up to 4 times faster than charge immobilization. Also, at -78 mV, Na current was inactivated 3 times faster than it recovered. Na inactivation and charge immobilization are linked, but proceed with high-order kinetics. The simplest scheme that accounts for their relation is .**GRAPHIC**. Depending on voltage, either state h2 (E > -45 mV) or h3 (E < -45 mV) becomes kinetically undetectable. A model of the Na channel is developed in which inactivation gains most of its voltage dependence by a coupling to the fast charge movement (activation). The model is quantitatively consistent with the results. The change of kinetics observed near -45 mV can be explained as an effect of the redistribution of charges on the inactivation process.