Contribution of extracellular negatively charged residues to ATP action and zinc modulation of rat P2X2 receptors

The divalent cation zinc is found in the mammalian CNS either tightly bound to proteins or as a smaller pool of free, chelatable zinc (Cuajungco and Lees 1997; Zatta et al. 2003). Genetic deletion of the zinc transporter ZnT3 in mice results in a dramatic decrease in the amount of zinc that can be detected in synaptic terminals but produces no obvious change in the behavior of mice (Palmiter et al. 1996; Cole et al. 1999; Salazar et al. 2005). Despite this observation, there is considerable evidence in support of the idea that synaptically released zinc plays a role as a regulator of synaptic transmission in the brain (Li et al. 2003). The most direct in vivo evidence for zinc as a physiological modulator in the brain is the observation that mice that express a mutant form of the glycine receptor a1 subunit gene (Glra1) that is zinc insensitive, but fully responsive to glycine, show a dramatic startle-prone phenotype, hyperekplexia (Hirzel et al. 2006). In addition to modulating the activity of glycine receptors in vivo, in vitro studies indicate that extracellular zinc can potentiate or inhibit the current responses of nicotinic acetylcholine receptors (Hsiao et al. 2001, 2006), N