Signalling at vanilloid TRPV1 channels

In this issue of the European Journal of Biochemistry, a prominent member of the transient receptor potential family of membrane channels, the transient receptor potential vanilloid type 1 protein (TRPV1), is the subject of three minireviews. TRPV1 channels were originally cloned while searching for a molecular target for two plant toxins: the fatty acid amide capsaicin, the well known pungent principle of hot chilli peppers (Capsicum sp.), and the phorboid resiniferatoxin, a much more potent vanilloid from Euphorbia sp. (Fig. 1). Both compounds contain a 3-methoxy-4-hydroxy-benzylamine (or ‘vanillamine’) moiety, previously shown to be a key determinant to observe potent activity in typical assays of vanilloid receptors. In fact, even before the cloning of TRPV1, strong evidence had been gained for the existence, in unmyelinized sensory fibers of the C type, of specific binding sites for capsaicin and resiniferatoxin, and extensive structure–activity studies had been performed for the former compound. It is now well established that other plant natural products, not necessarily containing a vanillyl structure, also activate TRPV1 receptors, although not as potently as capsaicin and resiniferatoxin. One of the major functions of this polymodal six transmembrane domain channel is, however, to act as one of several molecular transducers of painful physico-chemical stimuli, such as high temperatures (> 43°C) and acidity (pH < 6.5), and to intervene in inflammatory and thermal pain. The complex molecular regulation of the activity of TRPV1 is certainly key to understanding its role, while its detection, first in central neurons and more recently in epithelial cells, keratinocytes and (possibly) endothelial and glial cells, is likely to expand its participation to important (physio)pathological functions other than nociception. This possibility was also suggested by the finding of endogenous ligands of TRPV1 receptors, named ‘endovanilloids’, and led, among other things, to the proposition that these proteins, like other members of the TRP family, behave as receptor-operated channels in a large variety of conditions. The three minireviews in this issue of the journal focus on the most important biochemical issues concerned with the regulation of TRPV1 activity under both physiological and pathological conditions. Cortright & Szallasi provide a general overview of TRPV1 distribution, pharmacology and regulation by extracellular and intracellular signalling pathways, whereas Ferrer-Montiel and coworkers deal with the molecular aspects of TRPV1 gating and/or allosteric regulation by ligands. Finally, the article by van der Stelt & Di Marzo is a review of the new topic of endovanilloids, their biosynthetic and metabolic pathways, and their pharmacological actions. The intention is to provide the reader with state-of-the-art knowledge of what is starting to be seen as more than a temporarily ‘hot’ issue.