Vanilloids. While 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 among phosphorylation and dephosphorylation seems to determine the activity from 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 could be pharmacological possibilities to lower the sensory achieve of TRPV1. An intriguing strategy that appears increasingly feasible is interference using the fast trafficking of TRPV1 between cytosolic membrane compartments (endosomes, vesicles) as well as the cell membrane (Figure 1), which will lead to a reduction with 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 things like 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 growth factor and insulin-like development element because–together with TRPV1 and growth element receptors–it is portion 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 element attachment protein receptor also kind component 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). As a result, sensitization of TRPV1 is due not only to an enhancement of channel currents but also to a speedy 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 (and also other channels) to the cell surface is blocked by Tunicamycin Technical Information botulinum neurotoxin A (Morenilla-Palao et al., 2004), which may possibly explain why intradetrusor injection of botulinum neurotoxin A in individuals 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 Research Funds (FWF Grant L25-B05), the Jubilee Foundation with the Austrian National Bank (Grant 9858) and the Austrian Federal Ministry of Science and Investigation. 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.
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