The transduction of taste is a fundamental process that allows animals to discriminate nutritious from noxious substances. Three taste modalities, bitter, sweet, and amino acid, are mediated by G protein-coupled receptors that signal through a common transduction cascade: activation of phospholipase C β2, leading to a breakdown of phosphatidylinositol-4,5-bisphosphate (PIP ₂ ) into diacylglycerol and inositol 1,4,5-trisphosphate, which causes release of Ca ²⁺ from intracellular stores. The ion channel, TRPM5, is an essential component of this cascade; however, the mechanism by which it is activated is not known. Here we show that heterologously expressed TRPM5 forms a cation channel that is directly activated by micromolar concentrations of intracellular Ca ²⁺ ( K _1/2 = 21 μM). Sustained exposure to Ca ²⁺ desensitizes TRPM5 channels, but PIP ₂ reverses desensitization, partially restoring channel activity. Whole-cell TRPM5 currents can be activated by intracellular Ca ²⁺ and show strong outward rectification because of voltage-sensitive gating of the channels. TRPM5 channels are nonselective among monovalent cations and not detectably permeable to divalent cations. We propose that the regulation of TRPM5 by Ca ²⁺ mediates sensory activation in the taste system.

The vomeronasal organ (VNO) of terrestrial vertebrates plays a key role in the detection of pheromones, chemicals released by animals that elicit stereotyped sexual and aggressive behaviors among conspecifics. Sensory transduction in the VNO appears unrelated to that in the vertebrate olfactory and visual systems: the putative pheromone receptors of the VNO are evolutionarily independent from the odorant receptors and, in contrast to vertebrate visual and olfactory transduction, vomeronasal transduction is unlikely to be mediated by cyclic-nucleotide-gated channels. We hypothesized that sensory transduction in the VNO might instead involve an ion channel of the transient receptor potential (TRP) family, members of which mediate cyclic-nucleotide-independent sensory responses in Drosophila melanogaster and Caenorhabditis elegans and play unknown functions in mammals. We have isolated a cDNA (rTRP2) from rat VNO encoding a protein of 885 amino acids that is equally distant from vertebrate and invertebrate TRP channels (10–30% amino acid identity). rTRP2 mRNA is exclusively expressed in VNO neurons, and the protein is highly localized to VNO sensory microvilli, the proposed site of pheromone sensory transduction. The absence of Ca ²⁺ stores in sensory microvilli suggests that, in contrast to a proposed mechanism of activation of mammalian TRP channels, but in accord with analysis of TRP function in Drosophila phototransduction, the gating of TRP2 is independent from the depletion of internal Ca ²⁺ stores. Thus, TRP2 is likely to participate in vomeronasal sensory transduction, which may share additional similarities with light-induced signaling in the Drosophila eye.

The proton channel behind sour taste: Although many proteins that form ion channels in cell membranes have been described, none that selectively conduct protons into eukaryotic cells have been identified. Tu et al. used a genetic screen to pinpoint candidate genes that might encode such a protein from mouse taste receptor cells (see the Perspective by Montell). They identified the known protein otopetrin and showed that it conferred proton conductance when expressed in cultured human cells. Their results indicate that otopetrin may function in sensory recognition of sour (acidic) taste in humans and other organisms. Science , this issue p. 1047 ; see also p. 991

The transient receptor potential A1 (TRPA1) channel is the molecular target for environmental irritants and pungent chemicals, such as cinnamaldehyde and mustard oil. Extracellular Ca²⁺ is a key regulator of TRPA1 activity, both potentiating and subsequently inactivating it. In this report, we provide evidence that the effect of extracellular Ca²⁺ on these processes is indirect and can be entirely attributed to entry through TRPA1 and subsequent elevation of intracellular calcium. Specifically, we found that in a pore mutant of TRPA1, D918A, in which Ca²⁺ permeability was greatly reduced, extracellular Ca²⁺ produced neither potentiation nor inactivation. Both processes were restored by reducing intracellular Ca²⁺ buffering, which allowed intracellular Ca²⁺ levels to become elevated upon entry through D918A channels. Application of Ca²⁺ to the cytosolic face of excised patches was sufficient to produce both potentiation and inactivation of TRPA1 channels. Moreover, in whole cell recordings, elevation of intracellular Ca²⁺ by UV uncaging of 1-(4,5-dimethoxy-2-nitrophenyl)-EDTA-potentiated TRPA1 currents. In addition, our data show that potentiation and inactivation are independent processes. TRPA1 currents could be inactivated by Mg²⁺, Ba²⁺, and Ca²⁺ but potentiated only by Ba²⁺ and Ca²⁺. Saturating activation by cinnamaldehyde or mustard oil occluded potentiation but did not interfere with inactivation. Last, neither process was affected by mutation of a putative intracellular Ca²⁺-binding EF-hand motif. In conclusion, we have further clarified the mechanisms of potentiation and inactivation of TRPA1 using the D918A pore mutant, an important tool for investigating the contribution of Ca²⁺ influx through TRPA1 to nociceptive signaling.