Vanilloids. Even though 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 results in desensitization of TRPV1. As a balance in between phosphorylation and dephosphorylation seems to establish 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 achieve of TRPV1. An intriguing strategy that appears increasingly feasible is interference using the rapid trafficking of TRPV1 involving cytosolic membrane compartments (endosomes, vesicles) as well as the cell membrane (Figure 1), that will result in a reduction in the availability of TRPV1 channels on 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 contain regulatory, signalling and scaffolding proteins. For instance, 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 aspect and insulin-like growth aspect because–together with TRPV1 and development element receptors–it is part of a signal transduction complex that facilitates the translocation of TRPV1 for 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 kind component from 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 in addition to a rapid 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 (as well as other channels) for the cell surface is blocked by botulinum neurotoxin A (Morenilla-Palao et al., 2004), which may explain why intradetrusor injection of botulinum neurotoxin A in sufferers 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).AcknowledgementsWork performed in the laboratory was supported by the Zukunftsfonds Steiermark (Grant 262), the Austrian Scientific Investigation Funds (FWF Grant L25-B05), the Jubilee Foundation on the Austrian National Bank (Grant 9858) along with the Austrian Federal m-PEG7-thiol Cancer Ministry of Science and Analysis. I thank Ulrike Prometryn In Vivo Holzer-Petsche for critically reading the paper and Evelin Painsipp for graphical help.Conflict of interestThe author states no conflict of interest.
Menthol is often a fragrant monoterpenoid alcohol derived from peppermint (Mentha x piperita) oil. Its cooling sensation when topically applied.
