International Business Department           Liu Bojia           April 12, 2023

  Taste is one of the body's primary senses, and within it is a rich array of sensations, including sour, sweet, bitter, salty, and fresh (the perception of spiciness is not a taste sensation, but rather a nociceptive sensation that is transmitted via the heat-sensitive receptor TRPV1). Among them, bitterness not only helps us taste food, such as the bitter taste of coffee and bitter melon, but is also a natural defence mechanism of the body, with bitter receptors in taste bud cells signalling to us that substances may be toxic.

  According to existing research, bitter taste receptors belong to the TAS2R family, a class of G protein-coupled receptors. In humans, the TAS2R family includes 26 members and can detect more than 1,000 compounds. But as well as helping to detect bitterness on the tongue, TAS2Rs are also found in tissues outside the mouth, including the lungs and oesophagus, and with some studies suggesting that these receptors can be modulated by cholesterol and bile acids, there's still a lot we desperately need to know about bitter taste receptors.

  In today's issue of Nature, scientists from the University of North Carolina at Chapel Hill (USA) have revealed the first details of the protein structure of the bitter taste receptor, and in addition to this they have discovered how the bitter taste molecule binds to and activates the receptor, TAS2R.

  Within the TAS2R family, TAS2R14 is one of the more interesting members, as TAS2R14 alone recognises more than 100 bitter compounds. In the new study, the authors first examined the expression of TAS2R14 in different tissues, and they found that in addition to the tongue, TAS2R14 is widely expressed in cerebellum, skin, small intestine, and thymus tissues, with cerebellar tissues in particular showing 100-fold higher levels of TAS2R14 expression than the tongue, which is at the highest level of all types of tissues. TAS2R14 at these sites does not transmit bitter taste information, but is involved in other cell signalling pathways.

  The team then showed the protein structure of TAS2R14 with the help of biochemistry and cryo-electron microscopy and analysed how bitter taste molecules interact with it. They saw that when the bitter molecule comes into contact with TAS2R14, it embeds itself in a unique variant of the bitter taste receptor.

  As a result, TAS2R14 changes its shape and activates coupled G proteins. This activation signal causes a series of biochemical reactions downstream and transmits signals to tiny nerve fibres. The activation signal then travels with the facial nerves all the way to the taste cortex in the brain, where the brain receives and begins to process the bitter flavour information, so we can immediately feel the bitter taste in our mouth.

  The authors point out that this transfer of information from the taste bud cells to the taste cortex occurs almost instantaneously, which is why we spit out bitter foods we don't like as soon as we taste them.

  In addition to exogenous bitter molecules, the authors also found that TAS2R14 can also bind to endogenous molecules, like the aforementioned cholesterol can bind to the orthosteric site of TAS2R14, which, unlike the variant site where bitter molecules bind, normally binds to endogenous molecules and triggers downstream biological effects. Molecular dynamics experiments have shown that cholesterol binding to TAS2R14 leaves the bitter taste receptor in a semi-active state, which can be more readily activated by bitter taste molecules.

  In addition to cholesterol, bile acids secreted by the liver can also bind to TAS2R14. Bile acids have a similar structure to cholesterol, and they can also bind to the orthosteric site of TAS2R14. However, what downstream effects these two endogenous molecules produce upon association with TAS2R14 will need to be revealed by more future experiments.

  Bile acids and cholesterol have important roles in lipid metabolism, so the authors hypothesised that TAS2R14 is also involved in these metabolic processes and has been linked to a number of metabolic disorders, e.g., obesity, diabetes. And based on these new findings on bitter taste receptors, scientists can better develop drugs that target and regulate G protein-coupled receptors to help precisely treat related diseases.