Abstract
The sweet taste receptors T1r2 and T1r3 are included in the T1r taste receptor family that belongs to class C of the G protein-coupled receptors. Heterodimerization of T1r2 and T1r3 is required for the perception of sweet substances, but little is known about the mechanisms underlying this heterodimerization, including membrane trafficking. We developed tagged mouse T1r2 and T1r3, and human T1R2 and T1R3 and evaluated membrane trafficking in human embryonic kidney 293 (HEK293) cells. We found that human T1R3 surface expression was only observed when human T1R3 was coexpressed with human T1R2, whereas mouse T1r3 was expressed without mouse T1r2 expression. A domain-swapped chimera and truncated human T1R3 mutant showed that the Venus flytrap module and cysteine-rich domain (CRD) of human T1R3 contain a region related to the inhibition of human T1R3 membrane trafficking and coordinated regulation of human T1R3 membrane trafficking. We also found that the Venus flytrap module of both human T1R2 and T1R3 are needed for membrane trafficking, suggesting that the coexpression of human T1R2 and T1R3 is required for this event. These results suggest that the Venus flytrap module and CRD receive taste substances and play roles in membrane trafficking of human T1R2 and T1R3. These features are different from those of mouse receptors, indicating that human T1R2 and T1R3 are likely to have a novel membrane trafficking system.
Highlights
The sense of taste is both the guardian and guide for food intake, and it is vitally essential to animal body maintenance
We found that the Venus flytrap module (VFTM) of human T1R2 and human T1R3 (hT1R3) must both be present for appropriate membrane trafficking of hT1R2/hT1R3 and that the cysteine-rich domain (CRD) of hT1R3 contains a region related to the inhibition of hT1R3 membrane trafficking
To reliably determine the T1r2/T1r3 surface trafficking system, we introduced the c-Myc or FLAG epitope in the N-terminal domains of hT1R2, hT1R3, Mouse T1r2 (mT1r2), and mouse T1r3 (mT1r3) (CH2, FLAG tagged hT1R3 (FH3), Cm2, and Fm3, respectively)
Summary
The sense of taste is both the guardian and guide for food intake, and it is vitally essential to animal body maintenance. We focused on the surface trafficking systems of human and mouse sweet taste receptors. These receptors exhibit unique properties and are capable of binding various substances, such as sugars, amino acids, peptides, and artificial sweeteners. Understanding these features requires structure-function analyses of sweet taste receptors, which are a known heterodimer of G protein-coupled receptors (GPCRs) T1r2/T1r3 [9]. GPCRs are the largest superfamily of membrane receptors and are involved in the regulation of numerous physiological functions These integral membrane proteins share a common global topology comprised of seven transmembrane domains, an extracellular N-terminal domain, and an intracellular C-terminal domain and are classified in six large families (A–F) [10]. Our findings provide a novel perspective on evolutionary changes in taste reception system
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