Differential Inhibition of Glial K+ Currents by 4-AP

Abstract

Spinal cord astrocytes express four biophysically and pharmacologically distinct voltage-activated potassium (K+) channel types. The K+ channel blocker 4-aminopyridine (4-AP) exhibited differential and concentration-dependent block of all of these currents. Specifically, 100 μM 4-AP selectively inhibited a slowly inactivating outward current ( K SI) that was insensitive to dendrototoxin (≤10 μM) and that activated at −50 mV. At 2 mM, 4-AP inhibited fast-inactivating, low-threshold (−70 mV) A-type currents ( K A) and sustained, TEA-sensitive noninactivating delayed-rectifier-type currents ( K DR). At an even higher concentration (8 mM), 4-AP additionally blocked inwardly rectifying, Cs+- and Ba2+-sensitive K+ currents ( K IR). Current injection into current-clamped astrocytes in culture or in acute spinal cord slices induced an overshooting voltage response reminiscent of slow neuronal action potentials. Increasing concentrations of 4-AP selectively modulated different phases in the repolarization of these glial spikes, suggesting that all four K+ currents serve different roles in stabilization and repolarization of the astrocytic membrane potential. Our data suggest that 4-AP is an useful, dose-dependent inhibitor of all four astrocytic K+ channels. We show that the slowly inactivating astrocytic K+ currents, which had not been described as separate current entities in astrocytes, contribute to the resting K+ conductance and may thus be involved in K+ homeostatic functions of astrocytes. The high sensitivity of these currents to micromolar 4-AP suggests that application of 4-AP to inhibit neuronal A-currents or to induce epileptiform discharges in brain slices also may influence astrocytic K+ buffering.