Functions of potassium channels blocked by low micromolar 4-aminopyridine in the crayfish nervous system.

Abstract

4-aminopyridine (4-AP) is a potassium channel blocker that has been used to treat patients with multiple sclerosis and Lambert-Eaton disease. The concentration of this drug in the blood of patients was estimated to be in low or submicromolar range. Animal studies have shown that 4-AP at such low concentration selectively blocks a subset of channels in Kv1 or Kv3 families. The crayfish opener neuromuscular junction and ventral superficial flexor (VSF) preparations were used to examine functions of K+ channels blocked by low concentrations of 4-AP. At opener motor axons, intracellular recordings show that 4-AP could increase action potential (AP) amplitude, duration, and after-depolarization (ADP) at 10 μM. As 4-AP concentration was increased, in twofold steps, AP amplitude did not increase further up to 5mM. AP duration and ADP increased significantly mainly in two concentration ranges, 10-50 μM and 1-5mM. The effects of 50 μM 4-AP on the VSF were less consistent than that observed at the opener motor axons. 4-AP did not change AP amplitude of motor axons recorded with an extracellular electrode and change in AP repolarizing potential was observed in ∼25% of the axons. EPSP recorded simultaneously with AP showed an increase in amplitude with 4-AP treatment only in 30% of the axon-EPSP pairs. 4-AP also increased firing frequencies of ∼50% of axons. In four animals, 4-AP "awakened" the firing of APs from an axon that was silent before the drug. The mixture of positive and negative 4-AP effects summarized above was observed in the same VSF preparations in all cases (n=8). We propose that there is a significant diversity in the density 4-AP-sensitive potassium channels among motor axons of the VSF. Functional significance in the differences of 4-AP sensitivity of the two motor systems is discussed.