A “Cute” Desensitization of TRPV1
Filip Touska, Lenka Marsakova, Jan Teisinger and Viktorie Vlachova
Affiliation: Institute of Physiology AS CR, Videnska 1083, 142 20 Prague 4, Czech Republic.
Keywords: TRPV1 receptor, capsaicin, desensitization, analgesia, phorbol esters, camphor, anandamide, TRP channels, tachyphylaxis, ASIC receptor, phosphorylation, dephosphorylation, plethora, A-kinase, Piperine, PIP2, Asp178, Lys735, mutagenesis studies, bradykinin, scaffolding protein, ankyrin-repeat domain, calmodulin, polymodal activation, transmembrane spanning, Tyr671, HEK293, diabetic neuropathy, postherpetic neuralgia
Capsaicin and other vanilloids selectively excite and subsequently desensitize pain-conducting nerve fibers (nociceptors) and this process contributes to the analgesic (and thus therapeutically relevant) effects of these compounds. Such a desensitization process is triggered by the activation of the transient receptor potential vanilloid subtype 1 receptor channels (TRPV1) that open their cationic pores, permeable to sodium, potassium and calcium (Ca2+) ions. Depending on the duration of capsaicin exposure and the external calcium concentration, the Ca2+ influx via TRPV1 channels desensitizes the channels themselves, which, from the cellular point of view, represents a feedback mechanism protecting the nociceptive neuron from toxic Ca2+ overload. The ‘acute desensitization’ accounts for most of the reduction in responsiveness occurring within the first few (∼20) seconds after the vanilloids are administered to the cell for the first time. Another form of desensitization is ‘tachyphylaxis’, which is a reduction in the response to repeated applications of vanilloid. The wealth of pathways following TRPV1 activation that lead to increased intracellular Ca2+ levels and both forms of desensitization is huge and they might utilise just about every known type of signalling molecule. This review will not attempt to cover all historical aspects of research into all these processes. Instead, it will try to highlight some new challenging thoughts on the important phenomenon of TRPV1 desensitization and will focus on the putative mechanisms that are thought to account for the acute phase of this process.
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