Research on purinergic signaling has recently emphasized that a cascade of molecular interactions occur at the plasma membrane involving purinergic receptors, termed P2 for extracellular ATP/ADP, and P1 for extracellular adenosine. Nucleotideucleoside metabolizing ectoenzymes and nucle-otideucleoside transporters are also participating (Fig. 1). Altogether, they are responsible for triggering and sustaining the plethora of normal or pathological responses that neurons and glia elicit toward a single purine/pyrimidine stimulus in the CNS (Amadio et al. 2011; Volonte et al. 2012). Among the ionotropic P2X and metabotropic P2Y and P1 receptor subtypes so far identified, characterized, and cloned, the P2X3 receptor (P2X3R) was discovered in 1995 (Chen et al. 1995; Lewis et al. 1995) and soon after cloned from human (Garcia-Guzman et al. 1997). The P2X3 protein is predominantly localized on small- to medium-diameter C- and A5-fiber sensory neurons within the dorsal root ganglion and cranial sensory ganglia, and on their peripheral nerve terminals in tissues comprising skin, joints, and viscera.
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