Scientists Decipher the Perception of Bitter Taste. How Will This Help in the Development of New Drugs?

Taste Broken Down "Into Parts"

Sweet, salty, sour, bitter, and umami – the five tastes we can experience through taste buds on the tongue. Beyond that, by decoding the signals they send to the brain, we also receive warnings about inedible or even life-threatening substances (spoiled food, chemicals, poisons, and others).

However, Dr. Yoojoong Kim, one of the authors of the study cited below, admits that scientists still know very little about the detailed structure of receptors for sweet, bitter, and umami tastes. The researchers therefore meticulously analyzed the structure of the bitter taste receptor TAS2R14 (taste receptor type 2 member 14). They also identified where bitter-tasting compounds bind to it, how they activate it, and how cholesterol is involved in this process. To do so, they used a combination of biochemical and computational methods along with cryoelectron microscopy.

Uncovering the Key Point

How does the process work where a substance placed on the tongue is processed by the brain and identified as a bitter taste? And what new insights have been added to what we already knew?

The TAS2R14 protein belongs to the family of 26 type 2 taste receptors (TAS2R, also known as T2R). These are classified as G protein-coupled receptors (GPCRs), which are proteins located in the plasma membrane that facilitate the transfer of signals from the external environment of a cell to its interior. TAS2R14 can identify over 100 different compounds known as bitter tastants.

The researchers discovered that when these bitter-tasting compounds (found in food, chemicals, or medications) come into contact with the TAS2R14 receptor, they bind to its allosteric binding site, which induces a change in the receptor’s shape. This activates the attached G protein, whose activity then triggers a cascade of biochemical reactions in the taste bud cell.

The cell then sends nerve signals to the taste area of the brain cortex, where the brain processes the information and signals to the individual: “Caution, it’s bitter.” Subsequently, it evaluates the specific substance in terms of “safe/beneficial, consume” or “dangerous/unknown, do not consume.”

The allosteric binding site is located between TAS2R14 and the attached G protein, specifically in the α subunit of the G protein, and it is crucial for transmitting the signal into the taste cell. Bitter tastants act directly on TAS2R14 as positive allosteric modulators.

A Helping Hand from Cholesterol...

Cholesterol plays a role in the entire process, as it "nudges" TAS2R14 toward activation. It is simultaneously bound to the receptor but at a different site from the bitter tastants, in what is called the orthosteric pocket. Cholesterol’s role here is to prepare the TAS2R14 receptor for action, putting it into a pre-activated state, so the bitter tastant can easily activate it (cholesterol thus acts as an orthosteric agonist).

… And Perhaps Also from Bile Acids

Bile acids, which are structurally similar to cholesterol, have already been suggested in previous studies to bind to and activate TAS2R14. However, the mechanism of this binding and the specific location remained unclear. The researchers revealed that bile acids might also utilize the orthosteric pocket, similar to cholesterol.

Another avenue for research stems from the discovery of a connection between the allosteric binding site and the orthosteric pocket, a cavity where aromatic residues accumulate.

Candidates for New Drugs

While the exact role of bile acids or cholesterol in the TAS2R14 receptor remains unknown, scientists suggest that it may play a part in the metabolism of these substances or in relation to metabolic disorders such as obesity or diabetes.

According to Dr. Kim, the newly discovered allosteric binding site is expected to be the “key to discovering and designing drug candidates” that can directly regulate G proteins.

Editorial Team, Medscope.pro

Sources:

1. Kim Y., Gumpper R. H., Liu Y. et al. Bitter taste receptor activation by cholesterol and an intracellular tastant. Nature 2024; 628 (8008): 664–671, doi: 10.1038/s41586-024-07253-y.
2. Roth B. Researchers discover how we perceive bitter taste. UNC School of Medicine, 2024 Apr 10. Available at: https://news.unchealthcare.org/2024/04/researchers-discover-how-we-perceive-bitter-taste