Vanilloids. Despite the fact that 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 in between phosphorylation and dephosphorylation seems to identify the activity in 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 would be pharmacological possibilities to cut down the sensory get of TRPV1. An intriguing strategy that seems increasingly feasible is interference with all the speedy trafficking of TRPV1 involving cytosolic membrane compartments (endosomes, vesicles) and also the cell membrane (Figure 1), that will lead to a reduction of 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 involve regulatory, signalling and scaffolding proteins. As an 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 issue because–together with TRPV1 and development factor receptors–it is aspect of a signal Uridine-5′-diphosphate disodium salt web transduction complicated that facilitates the translocation of TRPV1 to 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 aspect on 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 only to an enhancement of channel currents but additionally to a fast translocation of TRPV1 from a cytosolic pool to 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 possibly clarify why intradetrusor injection of botulinum neurotoxin A in patients with urinary bladder overactivity reduces TRPV1- and purinoceptor P2X3-like immunoreactivity inside 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 inside the laboratory was supported by the Zukunftsfonds Steiermark (Grant 262), the Austrian Scientific Analysis Funds (FWF Grant L25-B05), the Jubilee Foundation of the Austrian National Bank (Grant 9858) and the Austrian Federal Ministry of Science and Study. I thank Ulrike Holzer-Petsche for critically reading the paper and Evelin Painsipp for graphical assistance.Conflict of interestThe author 118876-58-7 Epigenetics states no conflict of interest.
Menthol is actually a fragrant monoterpenoid alcohol derived from peppermint (Mentha x piperita) oil. Its cooling sensation when topically applied.
