, 2010; Newbolt et al., 1998; Roberts and Evans, 2006). Although

all functional P2X receptors undergo conformational changes that result in the opening of a cationic pore within milliseconds of ATP binding, some P2X receptors (notably Sorafenib P2X2, P2X4, and P2X7) also undergo additional slower conformational changes (Figure 4). Pore dilation follows several seconds of ATP activation and is characterized by increases in permeability to organic cations and several dyes (Khakh et al., 1999a; Khakh and Lester, 1999; North, 2002; Virginio et al., 1999). In other P2X receptors, notably P2X1 and P2X3, extended activation by ATP results in channel closure through desensitization. Pore dilation is of interest because Selleck Antidiabetic Compound Library it occurs over seconds, endowing P2X receptors with slow signaling capabilities and potentially providing the ability to release intracellular constituents such as ATP itself. Two mechanisms have been proposed for pore dilation (Figure 4). For P2X2, P2X4, and P2X7 receptors, pore dilation appears to involve an intrinsic conformational change in the protein itself (Chaumont and Khakh, 2008; Khadra et al., 2012; Yan et al., 2008, 2010, 2011). However, for natively expressed P2X7

channels, an accessory protein may also be required, and pannexin-1 channels may be involved in receptor pore Adenylyl cyclase dilation (Jiang et al., 2005; Pelegrin and Surprenant, 2006; Pelegrin and Surprenant, 2007; Surprenant et al., 1996) in a manner that varies with the particular splice variant being studied (Xu et al., 2012). In all cases, the dilated pore state is regulated by cellular processes and mechanisms that involve the C-terminal tail. In the case of P2X4 receptors, fast-scanning atomic force microscopy has been used to image

a slow conformational change that may underlie the phenomenon within single protein molecules (Shinozaki et al., 2009). Pore dilation may allow P2X receptors to function as intrinsic frequency detectors, by switching to the larger pore state with altered signaling upon repeated ATP activation (Khakh et al., 1999a). Recent data suggest that this particular state of P2X7 receptors may be involved in susceptibility to chronic pain (Sorge et al., 2012), raising the possibility that pore dilation of other P2X receptors in the brain may also mediate important slow responses. Further structural as well as physiological studies are needed to evaluate precisely how pore dilation and dynamic selectivity filters occur and what their functions are in vivo. P2X and nicotinic receptors undergo functional interactions (Barajas-López et al., 1998; Nakazawa, 1994; Nakazawa et al., 1991; Searl et al., 1998; Searl and Silinsky, 1998; Zhou and Galligan, 1998).