The functional role of the T1R family of receptors in sweet taste and feeding
Introduction
Over the last decade, the field of gustatory science has benefited greatly from the discovery of the receptor proteins that bind with sugars, synthetic sweeteners, some sweet-tasting proteins, and amino acids. For many years, it was known that such compounds generate activity in taste receptor cells, which in turn stimulate peripheral afferents projecting to the central gustatory pathway, but exactly how these responses were initiated remained unknown. It is now clear that in humans and the other mammals studied (mostly rodents), the receptor proteins responsible for the generation of the signals that are ultimately interpreted as “sweetness” and those leading to the so called “umami” taste associated with some l-amino acids, especially l-glutamate, are members of the T1R family consisting of a group of three Class-C G protein-coupled receptors: T1R1, T1R2, and T1R3. Each of these proteins is encoded by their respective genes: Tas1r1, Tas1r2, and Tas1r3 [4], [37], [46], [60], [61], [67], [83]. In the apical membrane of taste receptors cells, T1R3 combines with T1R1 to form a heterodimer (T1R1+3) that binds with l-amino acids and it combines with T1R2 to form a heterodimer (T1R2+3) that binds with sugars, a subset of D-amino acids, artificial sweeteners, and certain sweet-tasting proteins [54], [67], [116]. The exact binding profiles vary somewhat across the mammalian species studied and, as expected, these differences correlate with behavioral responses. For example, rats do not prefer the artificial sweetener aspartame nor treat it as sucrose-like [72], [90], and aspartame does not bind with the rat T1R2+3 [54], [67]. In the domestic cat the Tas1r2 is an unexpressed pseudogene, a finding that likely explains the lack of preference for sweeteners by this species [53].
Although it is uncontested that the T1R proteins play a large role in sweet and umami taste, it has been questioned whether these receptors are both necessary and sufficient for the generation of normal qualitative taste perception to their respective ligands. In other words, are there other taste receptors that bind with these same ligands and contribute to perception as well? Moreover, it has now been shown that the T1R proteins are expressed in non-gustatory tissue such as the nasal epithelium, the gut, the pancreas, and the brain. What is the functional role of these proteins in these other tissues? The following pages will review the literature in the context of addressing these questions.
Section snippets
Heterologous expression system: t1r2+3
Most of what is known about ligand selectivity of the T1R heterodimers is based on data from heterologous expression systems [54], [67], [116]. When cells from the Human Embryonic Kidney-293 line (HEK-293; or from the variant HEK293T) expressing promiscuous G-proteins are transfected with both rat T1R2 and T1R3, the application of stimuli from a panel of mono- and disaccharides, artificial sweeteners, and a subset of D-amino acids that are considered sweet-tasting by humans [85] and that
Gustatory tissue
Although T1R1, T1R2, and T1R3 can be found in taste buds of the anterior tongue, posterior tongue and palate, the relative expression of each T1R subunit varies across taste receptor fields [37], [45], [46], [51], [60], [61], [83]. In an initial study of expression patterns of T1R1 and T1R2 that combined mouse and rat tissues, T1R1 was found to be expressed in taste bud cells from fungiform papillae, which are found in the anterior two-thirds of the tongue and palate, and expressed to a lesser
Neural signaling in the gustatory system
The generation of knock-out (KO) mice in which the genes encoding for specific T1R proteins have been deleted has been the primary means by which the functional role of these receptors has been assessed. Such experiments do not yield data on the sufficiency of the T1R proteins in taste function, but they do provide a test of their necessity, notwithstanding the caveat of potential ontogenetic compensation associated with genetic knock-out preparations. Electrophysiological recordings from the
Nutrient sensing
The T1R2 and T1R3 proteins are also expressed in a variety of non-taste tissues including the gut, pancreas, and even the brain, raising the question as to what their functional roles in addition to taste might be. Given their uncontested ability to bind with mono and disaccharides in heterologous expression systems as well as in the gustatory epithelium, the expression of these proteins in non-taste tissue has been hypothesized to contribute to glucose sensing. Such a hypothesis enjoys some
Concluding remarks
On the whole, the available data clearly demonstrate that the T1R2 and T1R3 proteins are critical for normal qualitative perception of sugars and other compounds that humans describe as sweet and that rodent species find rewarding. There are nonetheless important nuances to these collective findings. Some T1R ligands have the potential to stimulate other receptors (e.g., the ability of some artificial sweeteners to bind with T2Rs) and this has to be considered in the interpretation of findings
Acknowledgments
We would like to thank Dr. Charles Zuker for generously supplying the T1R2 and T1R3 knock-out breeding pairs. Supported by NIH R01-DC004574 (A.C.S.).
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