No abstract

Recognition of sweet, bitter and umami tastes requires the non-vesicular release from taste bud cells of adenosine 5′-triphosphate (ATP), which acts as a neurotransmitter to activate afferent neural gustatory pathways1. However, how ATP is released to fulfill this function is not fully understood. Here we show that calcium homeostasis modulator 1 (CALHM1), a voltage-gated ion channel2,3, is indispensable for taste stimuli-evoked ATP release from sweet-, bitter- and umami-sensing taste bud cells. Calhm1 knockout mice have severely impaired perceptions of sweet, bitter and umami compounds, whereas sour and salty taste recognition remains mostly normal. Calhm1 deficiency affects taste perception without interfering with taste cell development or integrity. CALHM1 is expressed specifically in sweet/bitter/umami-sensing type II taste bud cells. Its heterologous expression induces a novel ATP permeability that releases ATP from cells in response to manipulations that activate the CALHM1 ion channel. Knockout of Calhm1 strongly reduces voltage-gated currents in type II cells and taste-evoked ATP release from taste buds without affecting the excitability of taste cells to taste stimuli. Thus, CALHM1 is a voltage-gated ATP release channel required for sweet, bitter and umami taste perception.

The hallmark features of type 2 mucosal immunity include intestinal tuft and goblet cell expansion initiated by tuft cell activation. How infectious agents that induce type 2 mucosal immunity are detected by tuft cells is unknown. Published microarray analysis suggested that succinate receptor 1 () is specifically expressed in tuft cells. Thus, we hypothesized that the succinate-Sucnr1 axis may be utilized by tuft cells to detect certain infectious agents. Here we confirmed that is specifically expressed in intestinal tuft cells but not in other types of intestinal epithelial cells, and demonstrated that dietary succinate induces tuft and goblet cell hyperplasia via Sucnr1 and the tuft cell-expressed chemosensory signaling elements gustducin and Trpm5. Conventional mice with a genetic Sucnr1 deficiency () showed diminished immune responses to treatment with polyethylene glycol and streptomycin, which are known to enhance microbiota-derived succinate, but responded normally to inoculation with the parasitic worm that also produces succinate. Thus, Sucnr1 is required for microbiota-induced but not for a generalized worm-induced type 2 immunity.

Functional diversification of taste cells is crucial for proper discrimination of taste qualities. We found homeodomain protein Skn-1a/Pou2f3 is expressed in sweet, umami, and bitter taste cells. The Skn-1a–deficient mice lacked electrophysiological and behavioral responses to sweet, umami, and bitter tastes, due to complete absence of sweet, umami, and bitter cells with concomitant expansion of sour cells. Skn-1a is critical for generating and balancing the diverse composition of taste cells.

Taste receptors function as one of the interfaces between internal and external milieus. Taste receptors for sweet and umami (T1R [taste receptor, type 1]), bitter (T2R [taste receptor, type 2]), and salty (ENaC [epithelial sodium channel]) have been discovered in the recent years, but transduction mechanisms of sour taste and ENaC-independent salt taste are still poorly understood. In addition to these five main taste qualities, the taste system detects such noncanonical “tastes” as water, fat, and complex carbohydrates, but their reception mechanisms require further research. Variations in taste receptor genes between and within vertebrate species contribute to individual and species differences in taste-related behaviors. These variations are shaped by evolutionary forces and reflect species adaptations to their chemical environments and feeding ecology. Principles of drug discovery can be applied to taste receptors as targets in order to develop novel taste compounds to satisfy demand in better artificial sweeteners, enhancers of sugar and sodium taste, and blockers of bitterness of food ingredients and oral medications.