Vanilloids. Although phosphorylation and relief from phosphatidylinositol-4,5-bisphosphate blockade sensitizes TRPV1 (Premkumar and Ahern, 2000; Vellani et al., 2001; Olah et al., 2002; Prescott and Julius, 2003), dephosphorylation by protein phosphatases leads to desensitization of TRPV1. As a balance involving phosphorylation and dephosphorylation appears to ascertain the activity on the channel (Jung et al., 2004; Mohapatra and Nau, 2005; Zhang and McNaughton, 2006; Lukacs et al., 2007), both interference with sensitization mechanisms and promotion of TRPV1 desensitization will be pharmacological possibilities to minimize the sensory get of TRPV1. An intriguing strategy that appears increasingly feasible is interference with the speedy trafficking of TRPV1 between cytosolic membrane compartments (endosomes, vesicles) along with the cell membrane (Figure 1), that will result in a reduction from the availability of TRPV1 channels around the cell surface (Morenilla-Palao et al., 2004; Planells-Cases et al., 2005; Zhang et al., 2005). Most membrane receptors reside in macromolecular complexes that include regulatory, signalling and scaffolding proteins. For example, A-kinaseanchoring protein-150 mediates phosphorylation of TRPV1 by protein kinase A and in this way contributes to thermal hyperalgesia (Jeske et al., 2008). Phosphoinositide 3-kinase is relevant to sensitization of TRPV1 by nerve development issue and insulin-like growth issue because–together with TRPV1 and growth issue receptors–it is component of a signal transduction complicated that facilitates the translocation of TRPV1 towards the plasma membrane (Van Buren et al., 2005; Zhang et al., 2005; Stein et al., 2006). Protein kinase C, Src kinase, snapin, synaptotagmin IX and soluble N-ethylmaleimide-sensitive factor attachment protein receptor also form element in the signal transduction complexes relevant to TRPV1 exocytosis (Morenilla-Palao et al., 2004; Planells-Cases et al., 2005; Van Buren et al., 2005; Zhang et al., 2005). Hence, sensitization of TRPV1 is due not simply to an enhancement of channel currents but also to a fast translocation of TRPV1 from a cytosolic pool towards the plasma membrane (Morenilla-Palao et al., 2004; Planells-Cases et al.,The pharmacological challenge of TRPV1 P Holzer2005; Van Buren et al., 2005; Zhang et al., 2005; Stein et al., 2006). The trafficking of TRPV1 (along with other channels) to the cell surface is blocked by botulinum neurotoxin A (Morenilla-Palao et al., 2004), which may perhaps explain why intradetrusor injection of botulinum neurotoxin A in individuals with urinary bladder overactivity reduces TRPV1- and purinoceptor P2X3-like immunoreactivity in the detrusor muscle and causes improvement of clinical and urodynamic parameters (Apostolidis et al., 2005). Intravesical administration of botulinum toxin likewise counteracts acetic acidevoked bladder overactivity in rats (Chuang et al., 2004).3-Bromo-7-nitroindazole Protocol AcknowledgementsWork performed in the laboratory was supported by the Zukunftsfonds Steiermark (Grant 262), the Austrian 6729-55-1 In Vivo Scientific Analysis Funds (FWF Grant L25-B05), the Jubilee Foundation with the Austrian National Bank (Grant 9858) as well as the Austrian Federal Ministry of Science and Research. I thank Ulrike Holzer-Petsche for critically reading the paper and Evelin Painsipp for graphical assistance.Conflict of interestThe author states no conflict of interest.
Menthol is a fragrant monoterpenoid alcohol derived from peppermint (Mentha x piperita) oil. Its cooling sensation when topically applied.