Molecular Mechanisms of Bitter and Sweet Taste Transduction

Abstract

G protein-coupled receptor d-phenylalanine taste sensitivity locus inositol trisphosphate phosphodiesterase cyclic nucleotide monophosphate phospholipase C saccharin taste sensitivity locus taste receptor cell diacylglycerol reverse transcription The sense of taste plays a critical role in the life and nutritional status of humans and other organisms. Human taste perception may be categorized according to four well known and widely accepted descriptors, sweet, bitter, salty, and sour (corresponding to particular taste qualities or modalities), and two more controversial qualities: fat and amino acid taste. The ability to identify sweet-tasting foodstuffs is particularly important as it provides us and other vertebrates with a means to seek out needed carbohydrates with high nutritive value. The perception of bitter, on the other hand, is essential for its protective value, enabling humans to avoid potentially deadly plant alkaloids and other environmental toxins. The focus of this review is on recent advances in our understanding of the transduction elements and signaling mechanisms underlying bitter and sweet taste transduction (see Fig.1). The sensations of bitter and sweet tastes are initiated by the interaction of sapid molecules (“tastants”) with G protein-coupled receptors (GPCRs)1 in the apical membranes of taste receptor cells (TRCs). TRCs are specialized epithelial cells with many neuronal properties including the ability to depolarize and form synapses. TRCs are typically clustered in groups of ∼100 within taste buds. The apical surface of TRCs, which makes contact with the oral cavity, is rich in convoluted microvilli containing GPCRs, ion channels, and other transduction elements. The basolateral aspect of TRCs contains ion channels and synapses with afferent taste nerves. “Data mining” of the National Center for Biotechnology Information DNA sequence data bases was used to identify an ∼25-member multigene family of TRC-expressed GPCRs, named T2Rs or TRBs (so-called as the second family of taste receptors identified) (1Adler E. Hoon M.A. Mueller K.L. Chandrashekar J. Ryba N.J.P. Zuker C.S. Cell. 2000; 10: 693-702Abstract Full Text Full Text PDF Scopus (1059) Google Scholar,2Matsunami H. Montmayeur J-P. Buck L.B. Nature. 2000; 404: 601-604Crossref PubMed Scopus (588) Google Scholar). The T2R/TRB GPCRs map to regions of human and mouse chromosomes implicated genetically in sensitivity to various bitter compounds (3Reed D.R. Nanthakumar E. North M. Bell C. Bartoshuk L.M. Price R.A. J. Hum. Genet. 1999; 64: 1478-1480Abstract Full Text Full Text PDF Scopus (112) Google Scholar, 4Capeless C.G. Whitney G. Azen E.A. Behav. Genet. 1992; 22: 655-663Crossref PubMed Scopus (55) Google Scholar, 5Lush I.E. Hornigold N. King P. Stoye J.P. Genet. Res. 1995; 66: 167-174Crossref PubMed Scopus (93) Google Scholar). T2R/TRB receptors are only distantly related to other GPCRs such as the V1R vomeronasal receptors and display 30–70% identity within the gene family. These receptors have the greatest conservation in their cytoplasmic loops and their adjacent transmembrane segments (predicted sites of G protein interaction) and the greatest divergence in their extracellular regions (potential regions of ligand binding). In rat and mouse T2R/TRB receptors are expressed in ∼15–20% of TRCs in taste buds of the circumvallate and foliate papillae and the palate but in very few TRCs in fungiform papillae (1Adler E. Hoon M.A. Mueller K.L. Chandrashekar J. Ryba N.J.P. Zuker C.S. Cell. 2000; 10: 693-702Abstract Full Text Full Text PDF Scopus (1059) Google Scholar). Based on in situ hybridization with mixed versus individual T2R/TRB probes it was concluded that most T2R/TRB receptors are expressed in the same TRCs (1Adler E. Hoon M.A. Mueller K.L. Chandrashekar J. Ryba N.J.P. Zuker C.S. Cell. 2000; 10: 693-702Abstract Full Text Full Text PDF Scopus (1059) Google Scholar, 2Matsunami H. Montmayeur J-P. Buck L.B. Nature. 2000; 404: 601-604Crossref PubMed Scopus (588) Google Scholar). T2R/TRB receptors are only found in TRCs positive for expression of gustducin (a G protein implicated in bitter taste) (see Fig. 2) (1Adler E. Hoon M.A. Mueller K.L. Chandrashekar J. Ryba N.J.P. Zuker C.S. Cell. 2000; 10: 693-702Abstract Full Text Full Text PDF Scopus (1059) Google Scholar). One murine T2R/TRB receptor (mT2R5), when expressed in heterologous cells, responded to bitter cycloheximide at a concentration comparable with the murine threshold for aversion (6Chandrashekar J. Mueller K.L. Hoon M.A. Adler E. Feng L. Guo W. Zuker C.S. Ryba N.J.P. Cell. 2000; 100: 703-711Abstract Full Text Full Text PDF PubMed Scopus (1104) Google Scholar). mT2R5 was found to couple selectively to α-gustducin versus other G protein α-subunits. Taste responses were obtained from only one other T2R/TRB-transfected cell; a human/mouse orthologous pair, hT2R4/mT2R8, apparently encodes a receptor responsive to denatonium and 6-n-propyl-2-thiouracil. However, the concen