, 1992; Evans et al., 1992; Silinsky et al., 1992). check details By this time, ATP receptors had also been subdivided as belonging to two major families: metabotropic P2Y receptors and ionotropic P2X receptors. With the subsequent cloning of the genes encoding P2X receptors came a new era. In this review, we focus on P2X receptor mediated ATP signaling in the brain, discussing general themes pertinent to mechanisms and neuromodulation at the molecular, cellular,

systems and disease levels. ATP activates a family of metabotropic P2Y and ionotropic P2X receptors. Collectively, the actions of ATP and its breakdown products produce responses that last from milliseconds to minutes, and even longer time scales through changes in gene regulation via second messengers. Signaling diversity is further increased by the fact that ATP receptors display a very broad range of ATP sensitivities, ranging from nanomolar in the case of P2Y receptors, to hundreds of micromolar for P2X7 receptors (Surprenant et al.,

1996). Thus, ATP receptors respond over remarkably broad spatiotemporal scales, and ATP signaling is very dynamic. The first P2X receptor genes were identified in 1994 (Brake et al., 1994; Valera et al., 1994) and within 2 years the whole family had been identified (Buell et al., 1996; Chen et al., 1995; Collo et al., 1996; Lê et al., 1997; Lewis et al., 1995; Soto et al., 1996; Surprenant et al., 1996). This was an exciting period that culminated with the realization that P2X receptors defined a unique protein family. Each of the homomeric P2X receptors also displays distinct functional FK228 mw properties (Figure 1; Table 1). The available data on the subunit composition and properties of heteromeric P2X receptors (Coddou et al., 2011) are not considered in depth here. P2X receptors are nonselective

cation channels with high Ca2+ permeability that carry a depolarizing current under standard physiological conditions. In some cells, P2X channels are also significantly permeable to anions. For example, the full length P2X5 receptor is permeable to Cl− (North, 2002). This remains the exception rather than the rule. Thus at its most fundamental level, P2X receptor mediated below neuromodulation starts with chemistry: ATP rapidly gates P2X receptor pores, triggering transmembrane fluxes of selected ions. The seven mammalian P2X subunits range from 379 (P2X6) to 595 (P2X7) amino acids in length. Each subunit contains two hydrophobic membrane-spanning segments (TM1 and TM2) separated by an ectodomain which contains ten conserved cysteine residues that form disulfide bonds. Representing the simplest known architecture for ligand-gated ion channels, P2X receptors adopt a relatively simple fold, with intracellular N and C termini and most of the molecule forming an extracellular loop.