T al., 2006; Bandell et al., 2007). In contrast to voltage-gated ion channels, TRP channels are normally only weakly sensitive to depolarization but open in response to changes in temperature, binding of ligands or other alterations on the channel protein (Clapham et al., 2005; Matta and Ahern, 2007; Nilius et al., 2007). As their activation is modulated by voltage modifications, TRP channels are included inside the large superfamily of voltage-gated-like ion channels (Bandell et al., 2007; Nilius et al., 2007). The ion selectivity differs markedly among the family of TRP channels, most of them getting non-selective cation channels, which can be also correct for TRPV1 with its high permeability for Ca2 (Caterina and Julius, 2001; Gunthorpe et al., 2002; Patapoutian et al., 2003; Garcia-Sanz et al., 2004). Interestingly, sustained exposure to agonists increases the Ca2 permeability of TRPV1 and causes pore dilation (Chung et al., 2008). TRPV1-bearing neurones are at some point overloaded by Ca2 , which in conjunction with other variables can outcome in mitochondrialswelling, long-lasting defunctionalization or even degeneration of the neurones (Szolcsanyi et al., 1975; Jancso et al., 1977, 1984, 1985; Wood et al., 1988; Szoke et al., 2002). Also, TRPV1 enables protons to enter the cell in an 780757-88-2 Protocol acidic D-?Glucose ?6-?phosphate (disodium salt) supplier atmosphere, which final results in intracellular acidification (Hellwig et al., 2004; Vulcu et al., 2004). Distinct members from the TRPV, TRPM and TRPA subunit households have turned out to become particularly relevant to nociception, thermosensation and chemaesthesis (Table 1). There is certainly emerging proof that members of other TRP channel subfamilies also contribute to thermo- and chemosensation, a lot as TRP channels are involved in sweet, bitter, sour and umami taste sensation (Zhang et al., 2003; Huang et al., 2006; Bandell et al., 2007; Montell and Caterina, 2007). It appears as if a dynamic balance involving phosphorylation and dephosphorylation of TRPV1 by Ca2 -calmodulindependent kinase II and calcineurin, respectively, controls the activation/desensitization state of the channel (Jung et al., 2004; Mohapatra and Nau, 2005). Also, desensitization seems to be associated to a depletion of phosphatidylinositol-4,5-bisphosphate (Liu et al., 2005; Stein et al., 2006), which attests to a dual function of this phosphoinositide in sensitization and desensitization of TRPV1 (Lukacs et al., 2007). The capacity of protons to sensitize TRPV1 to heat and other stimuli, around the one hand, and to activate TRPV1 per se, alternatively, is mediated by distinctive amino acid residues in the channel protein. Glu-600 around the extracellular side of transmembrane segment 5 is important for proton-induced British Journal of Pharmacology (2008) 155 1145sensitization of TRPV1, whereas Val-538 in the extracellular linker in between transmembrane segments three and 4, Thr-633 within the pore helix and Glu-648 within the linker in between the selectivity filter on the pore and transmembrane segment six are important for proton-induced gating of TRPV1 (Jordt et al., 2000; Ryu et al., 2007). Mutation on the latter amino acid residues selectively abrogates proton-evoked currents but preserves the present responses to capsaicin and heat and their potentiation by mildly acidic pH (Jordt et al., 2000; Ryu et al., 2007). Hence, the web pages inside the TRPV1 protein targeted by protons differ from those targeted by heat and chemical ligands (Jordt et al., 2000; Welch et al., 2000; McLatchie and Bevan, 2001; Gavva et al., 2004; Ryu et al.,.
