The functional role of the T1R family of receptors in sweet taste and feeding

Abstract

The discovery of the T1R family of Class C G protein-coupled receptors in the peripheral gustatory system a decade ago has been a tremendous advance for taste research, and its conceptual reach has extended to other organ systems. There are three proteins in the family, T1R1, T1R2, and T1R3, encoded by their respective genes, Tas1r1, Tas1r2, and Tas1r3. T1R2 combines with T1R3 to form a heterodimer that binds with sugars and other sweeteners. T1R3 also combines with T1R1 to form a heterodimer that binds with l-amino acids. These proteins are expressed not only in taste bud cells, but one or more of these T1Rs have also been identified in the nasal epithelium, gut, pancreas, liver, kidney, testes and brain in various mammalian species. Here we review current perspectives regarding the functional role of these receptors, concentrating on sweet taste and feeding. We also discuss behavioral findings suggesting that a glucose polymer mixture, Polycose, which rodents avidly prefer, appears to activate a receptor that does not depend on the combined expression of T1R2 and T1R3. In addition, although the T1Rs have been implicated as playing a role in glucose sensing, T1R2 knock-out (KO) and T1R3 KO mice display normal chow and fluid intake as well as normal body weight compared with same-sex littermate wild type (WT) controls. Moreover, regardless of whether they are fasted or not, these KO mice do not differ from their WT counterparts in their Polycose intake across a broad range of concentrations in 30-minute intake tests. The functional implications of these results and those in the literature are considered.

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.