Functional analysis of the sweet receptor TAS1R2 and TAS1R3

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Sweet taste is elicited by compounds of various chemical classes (Chon 1914). Natural sweeteners include sugars such as glucose and sucrose, sweet amino acids such as D-tryptophane, glycine, sweet proteins such as monellin, thauma-tin, but also some other chemically quite diverse compounds including stevioside and neohesperidin dihydrochalone (Schiffman and Gatlin 1993). Most relevant sugars and sweet amino acid are low potency sweeteners (Schiffman and Gatlin 1993). This likely serves as a quantity check because only high concentrations of these compounds can indicate food sources of nutritional value (Lindemann 1996). In addition, various high potency artificial sweeteners of various chemical structures such as saccharin, cyclamate, aspartame and alitame are known (Schiffman and Gatlin 1993). Interestingly, the perception of sweet compounds varies across species. Rodents, for example, do not perceive the sweetness of the sweet proteins monellin, thaumatin, and the artificial sweeteners aspartame and cyclamate which all taste sweet to humans (Sclafani and Abrams 1986, Tonosaki et al. 1997, Brouwer et al. 1973). Based on these observations some predictions for a genuine sweet receptor can be made: first, the receptor should be activated by a multitude of chemically diverse sweeteners. Second, the receptor should show a higher affinity for artificial sweeteners than for natural sweeteners. Third, the ligand profile of the human and rodent sweet taste receptor should reflect the observed species differences. In fact, the functional analysis of the human TAS1R2/TAS1R3 and rodent TaslrH Taslr3 heteromers showed that the receptors respond to sweeteners of multiple chemical classes (Nelson et al. 2001, Li et al. 2002). The human and the rodent receptor can be activated by the sweet mono- and disaccharides sucrose and fructose, sweet amino acids glycine and D-tryptophane, and by artificial sweeteners including saccharin and acesulfame K (Li et al. 2002). As predicted low concentration of the artificial sweeteners were needed for receptor activation, whereas carbohydrate sweeteners and sweet amino acids act at much higher concentrations (Nelson et al. 2001, Li et al. 2002). Notably, so far all tested compounds that are sweet to humans activate the human TAS1R2! TAS1R3 receptor (Li et al. 2002). Although the number of tested compounds is still limited these results show that the TAS1R2/TAS1R3 heteromer definitely mediates the majority of human sweet perception.

Consistent with the observed species differences the human receptor TAS1R2/TAS1R3 but not the mouse counterpart can be activated by monellin, thaumatin, cyclamate, and aspartame (Li et al. 2002) which are sweet for humans but not attractive for rodents (Sclafani and Abrams 1986, Tonosaki et al. 1997, Brouwer et al. 1973). Interestingly, it could be shown that the sweet blocker lactisole abolishes the response of cells transfected with the human TAS1R2/TAS1R3 but does not influence the response of the rat Taslr2!Taslr3 to sucrose (Li et al. 2002). This is consistent with the observation that lactisole blocks the sweet taste in humans but not in rats (Sclafani and Perez 1997). Therefore, the observed functional differences between the human and rodent receptor support the function of TAS1R2/TAS1R3 as a general sweet receptor.

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