Beyond Sweet and Savory: Scientists Discover The Sixth Taste

In the early 1900s, Japanese scientist Kikunae Ikeda proposed umami as a basic taste, alongside sweet, sour, salty, and bitter. The scientific community finally agreed with him around eight decades later. Scientists at the USC Dornsife College of Letters, Arts, and Sciences have discovered evidence of a sixth basic taste. Emily Liman, a neuroscientist at USC Dornsife, and her colleagues discovered that the tongue responds to ammonium chloride via the same protein receptor that signals a sour taste in a study published in Nature Communications (1^✔ ✔Trusted Source
The proton channel OTOP1 is a sensor for the taste of ammonium chloride

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“If you live in a Scandinavian country, you will be familiar with and may like this taste,” says Liman, professor of biological sciences. In some northern European countries, salt licorice has been a popular candy at least since the early 20th century. The treat counts among its ingredients salmiak salt, or ammonium chloride.

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OTOP1 Protein Revealed as the Key Player in the Tongue's Sour Taste Detection

For decades, scientists have known that ammonium chloride has a powerful effect on the tongue. Despite significant investigation, the specific tongue receptors that respond to it remain a mystery.

Liman and the study team believed they had found an answer. They discovered the protein responsible for detecting sour taste in recent years. OTOP1 is a protein that lies within cell membranes and generates a route for hydrogen ions to enter the cell.

Acids are made up primarily of hydrogen ions, and as every gourmand knows, the tongue perceives acid as sour. That's why lemonade (high in citric and ascorbic acids), vinegar (acetic acid), and other acidic foods have a tart aftertaste. The OTOP1 channel transports hydrogen ions from acidic substances into taste receptor cells.

Because ammonium chloride may change the concentration of acid — that is, hydrogen ions — within a cell, the researchers wondered if it could activate OTOP1.

To find out, they inserted the Otop1 gene into lab-grown human cells, causing the cells to create the OTOP1 receptor protein. They then measured the responses of the cells after exposing them to acid or ammonium chloride.

Small amounts of ammonia are released by ammonium chloride, which goes into the cell and raises the pH, making it more alkaline, resulting in fewer hydrogen ions. “We saw that ammonium chloride is a really strong activator of the OTOP1 channel,” Liman said. “It activates as well or better than acids.”

They used a technique that analyzes electrical conductivity, replicating how nerves convey a signal, to ensure that their discovery was more than a laboratory artifact. Using taste bud cells from normal mice and mice that had previously been genetically modified to not produce OTOP1, the researchers assessed how well the taste cells generated electrical reactions known as action potentials when exposed to ammonium chloride.

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OTOP1: Key in Detection of Ammonium Chloride and Behavioral Responses

Taste bud cells from wild-type mice showed a significant increase in action potentials after being exposed to ammonium chloride, whereas taste bud cells from mice lacking OTOP1 did not respond to the salt. This supported their theory that OTOP1 responds to salt by producing an electrical signal in taste bud cells.

The same was true when Courtney Wilson, another member of the research team, captured signals from the nerves that innervate taste cells. She observed nerves responding to ammonium chloride administration in normal mice but not in mice missing OTOP1.

The researchers then investigated how mice react when given the option of drinking normal water or water spiked with ammonium chloride. They disabled the bitter cells that contribute to the taste of ammonium chloride for these tests. Mice with a functional OTOP1 protein did not like the taste of ammonium chloride and did not drink it, whereas mice lacking the OTOP1 protein did not mind the alkaline salt, even at very high concentrations.

“This was the clincher,” Liman said. “It shows that the OTOP1 channel is essential for the behavioral response to ammonium.”

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Why Some Animals, Including Humans, Have a Unique Sensitivity to Ammonium Chloride

But the scientists were not finished. They wondered if other animals were susceptible to ammonium and used their OTOP1 channels to detect it. They discovered that the OTOP1 channel appears to be more susceptible to ammonium chloride in some species than in others. Human OTOP1 channels were also ammonium chloride sensitive.

So, what is the benefit of tasting ammonium chloride, and why has it been so evolutionary conserved? Liman hypothesizes that the capacity to taste ammonium chloride originated to aid species in avoiding dangerous biological substances containing large amounts of ammonium.

“Ammonium is found in waste products — think of fertilizer — and is somewhat toxic,” she explained, “so it makes sense we evolved taste mechanisms to detect it. Chicken OTOP1 is much more sensitive to ammonium than zebrafish.” Liman speculates that these variations may reflect differences in the ecological niches of different animals. “Fish may simply not encounter much ammonium in the water, while chicken coops are filled with ammonium that needs to be avoided and not eaten.”

She emphasizes, however, that this is preliminary data and that further research is needed to understand species differences in ammonium sensitivity and what makes OTOP1 channels from certain species sensitive and others less susceptible to ammonium.

They've made a start in this direction. "We identified a particular part of the OTOP1 channel — a specific amino acid — that's necessary for it to respond to ammonium," Liman told Reuters. "If we mutate this one residue, the channel is not nearly as sensitive to ammonium, but it still responds to acid." In other words, the ability of the OTOP1 channel to respond to ammonium must have been critical to the animals' survival.

The researchers intend to expand these investigations in the future to see whether ammonium sensitivity is conserved among other members of the OTOP proton family, which are expressed in other regions of the body, including the digestive tract.

And who knows what else? Ammonium chloride may join the other five basic flavors to bring the total to six.

Reference:

1. The proton channel OTOP1 is a sensor for the taste of ammonium chloride - (https://www.nature.com/articles/s41467-023-41637-4)

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