Transient receptor potential channels are involved in sensing chemical and physical changes inside and outside of cells. TRPV3 is highly expressed in skin keratinocytes, where it forms a nonselective cation channel activated by hot temperatures in the innocuous and noxious range. The channel has also been implicated in flavor sensation in oral and nasal cavities as well as being a molecular target of some allergens and skin sensitizers. TRPV3 is unique in that its activity is sensitized upon repetitive stimulations. -mediated inhibition and greatly facilitated the activation of TRPV3. We conclude that Ca 2؉ inhibits TRPV3 from both the extracellular and intracellular sides. The inhibition is sequentially reduced, appearing as sensitization to repetitive stimulations.
Members of the transient receptor potential (TRP)4 superfamily of cation channels have been recognized to play important roles in sensing various environmental changes inside and outside of cells as well as the whole organisms (1). In mammals, temperature sensing is thought to be accomplished through concerted actions of a minimum of six TRP channels, i.e. TRPA1, -M8, -V4, -V3, -V1, and -V2, each covering a defined temperature range from below 17°C to above 52°C (2, 3). However, the debate remains whether some of these channels, e.g. TRPA1, are really temperature-sensitive (4). In addition, TRPM2, -M4, and -M5 have shown temperature sensing in the presence of second messenger cofactors, such as ADP-ribose and Ca 2ϩ (5, 6). Although some of the thermosensitive TRP channels are clearly expressed and functional in sensory neurons, indicative of their actions in primary afferents, others have been localized in the non-nervous tissues, for example, TRPV3 and -V4 are expressed in skin keratinocytes (7,8) and TRPV3 is, in addition, expressed in the epithelium of tongue and nose (9). The TRPV3 null mice showed some deficits in sensing hot temperatures in the innocuous and noxious range but no other obvious sensory impairment (10). On the other hand, constitutively active mutations of TRPV3 have been linked to hair loss and atopic dermatitis-like skin lesions in rodents (11,12).In addition to temperature, the thermosensitive TRP channels are activated by a large number of structurally unrelated chemical ligands from exogenous as well as endogenous sources (13). This polymodal nature has become a common feature of the TRP channel family, implicating that multiple mechanisms and external stimuli may be involved in the activation and regulation of these channels. TRPV3 was first shown to be activated by 2-aminoethoxydiphenyl borate (2APB), a synthetic compound known to inhibit inositol 1,4,5-trisphosphate receptors and store-operated channels as well as many TRP channels (14, 15). It was soon discovered that a number of natural anti-irritants and flavor enhancers such as camphor, carvacrol, thymol, and eugenol, also use TRPV3 as one of their targets (9, 10). More importantly, cell signaling events leading to the activation of phospholipase C, phosphorylation by...