Block of potassium channels of the nodal membrane by 4-aminopyridine and its partial removal on depolarization

Abstract

Voltage clamp experiments were done on single myelinated nerve fibres of the frog,Rana esculenta. 53 μM 4-aminopyridine (4-AP) reducedI _K to about one-fifth if tested with infrequent (1/min) and short (10 ms) depolarizing pulses; the onset time constant under these circumstances was ca. 160 s (14–15° C). After prolonged treatment the effect was virtually irreversible. At equilibrium with 4-AP, increasing the frequency of short pulses removed part of the block, the block removal accelerating with inceasing pulse duration and frequency. In 53 μM 4-AP unblocking of K channels during long (0.8 s) depolarizing pulses proceeded with a time constant, τ _r , of ca. 0.2 s. Restoration of block at the resting potential proceeded with a much larger time constant, τ′ _r , of ca. 1 min. The stationary fraction,r _∞, of K channels conducting in 53 μM 4-AP was 0.66, 0.41, and 0.24 at V=120, 50, and 0 mV, respectively. In a series of experiments with [4-AP] varying between 13.3 and 848 μM, τ _r decreased from 0.25 to 0.10 s (V=130 mV, ca. 17°C) whiler _∞ followed the empirical relation 1/r _∞=1+c _t +c _v exp(−0.77 EF/RT) with E=V-70 mV.c _t andc _v are dimensionless quantities that increase with [4-AP] and reflect the voltage-independent and voltage-dependent component, respectively, of block. Block of K channels and partial removal are also observed with inwardI _K at raised [K⁺]₀. Removal proceeds on depolarization even ifI _K is additionally but temporarily suppressed by tetraethylammonium. Hence neither direction nor amplitude ofI _K but only the pulse potential seems to determine the extent of block for a given [4-AP].