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 results in desensitization of TRPV1. As a balance involving phosphorylation and dephosphorylation seems to determine the activity of the channel (Jung et al., 2004; Mohapatra and Nau, 2005; Zhang and McNaughton, 2006; Lukacs et al., 2007), each interference with sensitization mechanisms and promotion of TRPV1 desensitization will be pharmacological opportunities to decrease the sensory acquire of TRPV1. An intriguing method that seems increasingly feasible is interference with the fast trafficking of TRPV1 in between cytosolic membrane compartments (endosomes, vesicles) and also the cell membrane (Figure 1), that will lead to a reduction from 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 Relebactam References macromolecular complexes that involve 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 aspect and insulin-like growth factor because–together with TRPV1 and growth factor receptors–it is component of a signal transduction complicated 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 issue attachment protein receptor also type aspect with 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). Thus, sensitization of TRPV1 is due not only to an enhancement of channel currents but also 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 (and also other channels) for the cell surface is blocked by botulinum neurotoxin A (Morenilla-Palao et al., 2004), which could explain why intradetrusor injection of botulinum neurotoxin A in patients with urinary bladder overactivity reduces TRPV1- and purinoceptor P2X3-like immunoreactivity within 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 (Ethoxyacetic acid MedChemExpress Chuang et al., 2004).AcknowledgementsWork performed in the laboratory was supported by the Zukunftsfonds Steiermark (Grant 262), the Austrian Scientific Research Funds (FWF Grant L25-B05), the Jubilee Foundation in the Austrian National Bank (Grant 9858) and also 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 often a fragrant monoterpenoid alcohol derived from peppermint (Mentha x piperita) oil. Its cooling sensation when topically applied.
