Microglial cells have important functions during regenerative processes after brain injury. It is well established that they rapidly respond to damage to the brain tissue. Stages of activation are associated with changes of cellular properties such as proliferation rate or expression of surface antigens. Yet, nothing is known about signal substances leading to the rapid changes of membrane properties, which may be required to initiate the transition from one cell stage into another. From our present study, using the patch-clamp technique, we report that cultured microglial cells obtained from mouse or rat brain respond to extracellularly applied ATP with the activation of a cation conductance. Additionally, in the majority of cells an outwardly directed K+ conductance was activated with some delay. Since ADP, AMP, and adenosine (in descending order) were less potent or ineffective in inducing the cation conductance, the involvement of a P2 purinergic receptor is proposed. The receptor activation is accompanied by an increase of cytosolic Ca2+ as determined by a fura-2-based Ca(2+)- imaging system. This ATP receptor could enable microglial cells to respond to transmitter release from nerve endings with ATP as a transmitter or cotransmitter or to the death of cells with resulting leakage of ATP.