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 microM 4-AP selectively inhibited a slowly inactivating outward current (K(SI)) that was insensitive to dendrototoxin (< or = 10 microM) 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 Ba(2+)-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.