The vanilloid transient receptor potential channel TRPV1 is a tetrameric six-transmembrane segment (S1-S6) channel that can be synergistically activated by various proalgesic agents such as capsaicin, protons, heat, or highly depolarizing voltages, and also by 2-aminoethoxydiphenyl borate (2-APB), a common activator of the related thermally gated vanilloid TRP channels TRPV1, TRPV2, and TRPV3. In these channels, the conserved charged residues in the intracellular S4 -S5 region have been proposed to constitute part of a voltage sensor that acts in concert with other stimuli to regulate channel activation. The molecular basis of this gating event is poorly understood. We mutated charged residues all along the S4 and the S4 -S5 linker of TRPV1 and identified four potential voltagesensing residues (Arg 557 , Glu 570 , Asp 576 , and Arg 579 ) that, when specifically mutated, altered the functionality of the channel with respect to voltage, capsaicin, heat, 2-APB, and/or their interactions in different ways. The nonfunctional chargereversing mutations R557E and R579E were partially rescued by the charge-swapping mutations R557E/E570R and D576R/ R579E, indicating that electrostatic interactions contribute to allosteric coupling between the voltage-, temperature-and capsaicin-dependent activation mechanisms. The mutant K571E was normal in all aspects of TRPV1 activation except for 2-APB, revealing the specific role of Lys 571 in chemical sensitivity. Surprisingly, substitutions at homologous residues in TRPV2 or TRPV3 had no effect on temperature-and 2-APBinduced activity. Thus, the charged residues in S4 and the S4 -S5 linker contribute to voltage sensing in TRPV1 and, despite their highly conserved nature, regulate the temperature and chemical gating in the various TRPV channels in different ways.The vanilloid receptor TRPV1 is a member of the vanilloid subgroup (TRPV) of the transient receptor potential (TRP) 2 channel family that functions as a multimodal signal transducer of noxious stimuli in the mammalian somatosensory system (1). This nonselective cation channel can be activated by noxious thermal stimuli (Ͼ43°C), acidic pH (Ͻ6.8) or the alkaloid irritant capsaicin. Moreover, at room temperature (24°C) and pH 7.3, TRPV1 behaves as a voltage-gated outwardly rectifying channel because it can be activated, in the absence of any agonist, by depolarizing voltages (Ͼ60 mV) (2). All of these stimuli act strongly synergistically: capsaicin lowers the threshold for heat activation, capsaicin-evoked currents are augmented by heat or by lowering pH (3), whereas heat, protons, and capsaicin enhance the efficacy and sensitivity of voltage-induced activation (2, 4, 5).The existence of distinct functional domains through which disparate stimuli converge on the channel protein to open/ close its ion-conducting pore is thought to underlie the polymodal nature of not only TRPV1 but also its related, temperature-sensitive, protein family members: heat-activated TRPV2, TRPV3, TRPV4, and cold-activated TRPA1 and melastatin TRP chann...

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 (Ca(2+)) ions. Depending on the duration of capsaicin exposure and the external calcium concentration, the Ca(2+) 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 Ca(2+) 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 Ca(2+) 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.

Background: TRPA1 channel is modulated by Ca 2ϩ , but the molecular mechanisms are unclear. Results: Mutations in the distal C-terminal acidic domain altered Ca 2ϩ dependence of TRPA1. Conclusion: The C-terminal acidic cluster is involved in the Ca 2ϩ -induced potentiation and inactivation of TRPA1. Significance: Identification of the Ca 2ϩ -dependent domain is important for understanding the role of TRPA1 in chemical nociception.