The electrophysiological properties of ameboid microglia from rodent brain are dominated by inwardly rectifying potassium channels and by the lack of outward currents. This channel pattern results in a distinct physiological behavior: depolarizing events, e.g. following adenosine triphosphate receptor activation, can lead to a long lasting membrane depolarization. Here we address the question whether this resting K+ channel activity can be modulated. Intracellular application of guanosine 5'-O-(3-thiotriphosphate) induced an outward current and led to a complete disappearance of the inward current inward rectifier potassium current as measured with the patch clamp technique. Moreover, an elevation in cytosolic calcium concentration (to 1.6 microM) via intracellular perfusion reversibly blocked the inward current. The inhibition of inward currents by guanosine 5'-O-(3-thiotriphosphate) could be enhanced by additional adenosine triphosphate receptor activation. Adenosine triphosphate or tumor necrosis factor receptor activation alone could lead to a transient partial block of the inward rectifier and to the transient appearance of a delayed outward current. We conclude that the activity of the microglia K+ channels and thus the physiological behavior of microglia can be modulated on a time scale of seconds by receptor activation and distinct intracellular pathways.