Comprehensive Analysis of Mouse Bitter Taste Receptors Reveals Different Molecular Receptive Ranges for Orthologous Receptors in Mice and Humans

Abstract

One key to animal survival is the detection and avoidance of potentially harmful compounds by their bitter taste. Variable numbers of taste 2 receptor genes expressed in the gustatory end organs enable bony vertebrates (Euteleostomi) to recognize numerous bitter chemicals. It is believed that the receptive ranges of bitter taste receptor repertoires match the profiles of bitter chemicals that the species encounter in their diets. Human and mouse genomes contain pairs of orthologous bitter receptor genes that have been conserved throughout evolution. Moreover, expansions in both lineages generated species-specific sets of bitter taste receptor genes. It is assumed that the orthologous bitter taste receptor genes mediate the recognition of bitter toxins relevant for both species, whereas the lineagespecific receptors enable the detection of substances differently encountered by mice and humans. By challenging 34 mouse bitter taste receptors with 128 prototypical bitter substances in a heterologous expression system, we identified cognate compounds for 21 receptors, 19 of which were previously orphan receptors. We have demonstrated that mouse taste 2 receptors, like their human counterparts, vary greatly in their breadth of tuning, ranging from very broadly to extremely narrowly tuned receptors. However, when compared with humans, mice possess fewer broadly tuned receptors and an elevated number of narrowly tuned receptors, supporting the idea that a large receptor repertoire is the basis for the evolution of specialized receptors. Moreover, we have demonstrated that sequence-orthologous bitter taste receptors have distinct agonist profiles. Species-specific gene expansions have enabled further diversification of bitter substance recognition spectra.The plethora of natural compounds that taste bitter for humans comprises numerous chemicals with pharmacological activities that can make them powerful toxins, such as the alkaloids strychnine and colchicine or the sesquiterpene lactone picrotoxinin (1). However, compounds believed to exert health-beneficial effects such as the antioxidative phytoestrogen genistein from soy (2), the analgesic drug acetaminophen (3), or various polyphenols also taste bitter (4). To avoid ingestion of bitter substances that would pose a threat to organisms, efficient recognition and rejection mechanisms have developed throughout the animal kingdom. In bony vertebrates (Euteleostomi), the avoidance of bitter compounds is centered on taste receptors that detect potentially harmful substances with high accuracy and adequate sensitivity (5). Vertebrate bitter taste receptors, called taste 2 receptors (TAS2R (human) or Tas2r (murine)), 2 are G protein-coupled receptors only remotely related to other classes of this large and enormously versatile receptor family (6 -10). During evolution the first Tas2r genes appeared in the genomes of bony fish (11). In higher vertebrates frequent independent expansions and pseudogenization events resulted in differently sized Tas2r gene repertoires (12). Cons...

Taste buds: cells, signals and synapses

“…This study showed, for instance, that T2R3 responds to only a single compound (out of 94 different natural and synthetic compounds tested), whereas T2R14 responds to at least 33 compounds. Conversely, a single bitter compound often can activate multiple different T2Rs 51–54 . For example, quinine activates as many as nine different human T2Rs, whereas acetaminophen — an analgesic — stimulates just one human T2R 51 .…”

“…Presumably, this redundancy evolved to ensure the detection of potentially toxic (bitter-tasting) chemicals and thus prevent the consumption of harmful foods. An evolutionary note in this context is that orthologous receptors in mice and humans often are responsive to very different bitter tastants 54 , which suggests that receptors have been reassigned to ecologically relevant compounds and that the gene family has been subjected to selective pressures 55 . Many T2Rs exhibit functional polymorphisms that result in varying abilities to taste particular compounds 56 , and these polymorphisms may underlie differences in food preference 57 (BOX 3).…”

Functional characterization of the TAS2R38 bitter taste receptor for phenylthiocarbamide in colobine monkeys

“…This result was consistent with the PTC-tolerant behaviour of colobines. The critical amino acid positions for human TAS2R38 functionality [17] are not altered in the colobine TAS2R38 receptor.…”

Use of Adult Sensory Panel to Study Individual Differences in the Palatability of a Pediatric HIV Treatment Drug

“…That many bitter compounds do not act through known taste receptors 72 , suggests other receptor families and pathways exist 7,72 . This research also lays the foundation for objectively measuring individual differences—the hallmark of human perception—by not only panelists but also patients.…”