Molecular identification of purine receptors, particularly the P2X receptor channels of several types, in the late 90's lead researchers to identify their roles in the brain because many subtypes were found there. Except for the first identification of the fast excitatory synaptic transmission mediated by ATP in the medial habenula of rats (Edwards et al., 1992), such demonstration in the mammalian brain remained highly limited, mostly due to the extremely rapid breakdown of ATP to adenosine. In the brain slice preparation, we found that ATP (presumably released from astrocytes) triggers Ca-dependent action potential-independent release by activating presynaptic P2X2/3 receptors, which is followed by reduction of action potential-dependent release through activating presynaptic adenosine A1 receptors (Kato & Shigetomi, 2001; Shigetomi & Kato, 2004). We proposed that spatially limited colocalization of P2X and A1 receptors and ectonucleotidase enables ATP to exert dual functions and dubbed this system "purine signaling complex in the brain synapses," which later found in many brain structures (Kawamura et al., 2004) and also in non-mammalian species (Wakisaka et al., 2017).