, 2001), but deleting ASIC2 or ASIC3 has only subtle effects on the activity of mechanoreceptor fibers (Price et al., 2000 and Price et al., 2001). Moreover, neither ASIC2 nor ASIC3 is essential for MeT currents studied in cultured DRG neurons (Drew et al., 2004). Collectively, these investigations indicate that no single ASIC subunit is essential for the function of mechanoreceptor neurons in mice and suggest that the function of such neurons is robust to genetic deletion buy PF-02341066 of channel proteins. In principle, genetic deletion of a shared auxiliary subunit could reveal more severe deficits in behavioral and cellular responses

to touch because such proteins might affect the function of multiple channel-forming subunits. The impact of genetic deletion of SLP3 illustrates the power of this idea (Wetzel et al., 2007). SLP3 (also known as STOML3) is a stomatin-like protein that binds to both ASIC2 and ASIC3 and alters the activity of ASIC channels in heterologous cells. It is orthologous to the C. elegans protein MEC-2, which is required for MeT currents in vivo and enhances MEC-4-dependent currents in heterologous cells ( Goodman

et al., 2002, Huang and Chalfie, 1994 and O’Hagan et al., 2005). Genetic deletion of SLP3 decreases the proportion of mechanically sensitive Aβ and Aδ fibers that innervate the skin and the proportion of dissociated DRG neurons with mechanosensitive currents ( Wetzel et al., 2007). Additionally, loss of SLP3 disrupts texture sensing. These data suggest that many, but not all mechanoreceptors depend on SLP3 and its DEG/ENaC binding partners to detect mechanical stimuli. DAPT mouse Mirroring the effects of single ASIC gene deletions are those of TRP channel gene deletions: loss of a single channel gene has only subtle effects on somatosensory nerve fiber function and no single TRP channel gene deletion leads to a loss of mechanosensitivity in an individual fiber class (Kwan et al., 2006, Kwan et al., 2009, Liedtke and Friedman,

2003 and Suzuki et al., 2003a). But, loss of TRP channel proteins has clear effects on the response of nociceptors to inflammation. Here, we provide three examples. First, noxious chemical agents such as mustard oil potentiate behavioral responses to mechanical stimuli, an effect which is muted in TRPA1 knockout mice (Bautista et al., 2006). Loss 4-Aminobutyrate aminotransferase of TRPA1 also disrupts sensitization produced by injection of bradykinin, a peptide released by damaged tissue (Kwan et al., 2009). Second, genetic deletion of TRPV4 has subtle effects on behavioral and neural responses to mechanical cues (Chen et al., 2007 and Suzuki et al., 2003a) but produces significant deficits in inflammation-induced sensitization. Compounds induced by inflammation (prostaglandin E2 and serotonin) decrease the threshold for mechanical activation of C fiber nociceptors in wild-type, but not in TRPV4−/− ( Alessandri-Haber et al., 2005 and Chen et al., 2007).