AbstractActivation of postsynaptic P2X receptors, which occur in many synapses in the central nervous system, following vesicular adenosine triphosphate (ATP) released from presynaptic terminals contributes to the fast excitatory neurotransmission. Postsynaptic P2X receptors mediate fast excitatory postsynaptic currents in synapses located in various brain regions, including medial habenula, hippocampus, and cortex. Synaptic stimulation of P2X receptors can trigger substantial Ca2+entry and cytosolic Ca2+signaling at the resting membrane potential due to a high Ca2+permeability of P2X receptors. In addition, P2X receptors dynamically interact withN‐methylD‐aspartate (NMDA) receptors,γ‐aminobutyric acid (GABA) receptors, and nicotinic acetylcholine (ACh) receptors. Activation of P2X receptors in the course of synaptic transmission has multiple modulatory effects on synaptic plasticity, either inhibiting or facilitating the long‐term changes of synaptic strength depending on physiological context.WIREs Membr Transp Signal2012,1:297–309. doi: 10.1002/wmts.28For further resources related to this article, please visit theWIREs website.