by Xiaomeng Han

How many times have you heard the age-old proverb “When life gives you lemons, make lemonade” and pulled yourself together to face life’s difficulties with a can-do attitude? But have you ever imagined if life gives lemons (literally) to lab mice that they could make lemonade as well? In a study published last fall, Dr. Jin Zhang and colleagues in Prof. Charles Zuker’s lab at Columbia University revealed how taste sensation is passed to the brain in mice and discovered a protein (a complex biomolecule that plays an important role in our body) that is the main sour sensor in the tongue. When scientists manipulated this sour sensor protein with a gene-editing technique, mice enjoyed sour tastes as much as sweet tastes, as if the lemons given to them were magically turned into lemonade!

How is taste sensation passed from the tongue to the brain?

Sour taste from food like lemons is among the five different tastes (sweet, bitter, sour, salty, and savory) humans can perceive. Taste receptor cells (TRCs) located on the surface of the tongue are responsible for sensing and differentiating these five tastes (a more detailed introduction can be found in a previous blog article). TRCs are divided into several types, each with the ability to detect different tastes. For example, sweet and sour tastes are detected by two separate types of TRCs. When TRCs detect tastes, they send signals to their partner neurons (cells that transmit signals in our nervous system) in a place called the geniculate ganglion inside a small canal of the temporal bone of the skull. These neurons will then relay taste information to our brain. A theory called the “labeled line model” proposes that each type of TRC specialized for one taste connects to only one type of neuron in the geniculate ganglion (Figure 1). This “one-taste, one-TRC, one-neuron” concept is just like how in a computer, sound is transmitted from the microphone and video by different electric circuits. In Dr. Zhang’s study mentioned above, it was confirmed that the geniculate ganglion in mice indeed has five types of neurons, each expressing a specific gene and each tuning to a specific taste (sweet, bitter, sour, salty or savory).  

 

 

The sour sensor protein – the proton channel Otop1 

Given that different types of TRCs detect different tastes, it is natural to speculate they have sensors specialized for different tastes. Indeed, they each possess unique sensor proteins that can detect the taste substance they are responsible for. For example, sweet-sensing and bitter-sensing TRCs each have their corresponding sensor proteins that detect either sweet or bitter substances to help them do their job (also previously explained). 

Although sweet and bitter sensor proteins have been identified, the sour sensor protein was previously unknown. Many kinds of proteins have been proposed as potential candidates, but none of them were validated until a new protein called Otopetrin1 (Otop1) was identified in a 2018 study led by Dr. Yu-Hsiang Tu. Otop1 is a protein present at high levels only in sour-sensing TRCs. It is found in the cell membrane that separates the inside of TRCs from the outside environment. Otop1 functions as a channel, which means it allows certain substances to pass through the cell membrane. In this case, Otop1 passes positively charged protons, which are highly concentrated in sour food and drinks. When protons go into TRCs through Otop1, an electrical current will be produced across the cell membrane, which makes these sour-sensing TRCs very “excited”. The “excited” TRCs will then send signals to neurons responsible for sourness in the geniculate ganglion, and the signals will eventually be relayed to the brain. In Dr. Zhang’s study, when the gene responsible for Otop1 production was deleted in mice (meaning that the animal doesn’t have any Otop1 in their body), the mice lost their ability to detect sourness, demonstrating that Otop1 is the sensor protein for sour detection.

Otop1 in sweet-sensing cells turns sourness into sweetness

The loss of sour detection ability caused by deletion of Otop1 showed that Otop1 is required for TRCs to detect sourness, but it remained unclear if Otop1 by itself could perform the sour sensing task. In order to test whether Otop1 alone is sufficient for detecting sourness, Dr. Zhang and colleagues designed an intriguing experiment. With the help of the gene editing technique CRISPR/Cas9, sweet-sensing TRCs in mice were engineered to possess not only the normal sweet sensor protein, but also the sour sensor protein Otop1 (which under normal conditions is absent in sweet-sensing TRCs). With both sensors, the mice’s sweet-sensing TRCs can now detect both sweetness and sourness (Figure 2). 

 

 

Based on the “one-taste, one-TRC, one-neuron” theory mentioned before, these sweet-sensing TRCs will only send signals to, and thus activate, the neurons responsible for sweetness in the geniculate ganglion, which will then relay sweet information to the brain. This model led Dr. Zhang and colleagues to predict that these special mice will sense sweetness from both tastes that are truly sweet as well as those that are actually sour. Just as they expected, nearly all the neurons activated in the geniculate ganglion when the mice were given sweet water were also activated when the mice were given sour water. Based on these findings, scientists also speculate that these mice may enjoy sour food as much as sweet food because sourness now tastes “sweet”.

The findings from Dr. Jin Zhang and colleagues’ work confirmed for the first time that the protein Otop1 is both necessary and sufficient for sourness detection in TRCs, meaning it is the real sour sensor protein–at least in mice. If further study on Otop1 shows that it is also the sour sensor protein in humans, Otop1 would be a good entry point to further our understanding of sour taste perception and guide our potential manipulation of our sour taste perception. For example, genetic study of Otop1 may reveal people have slightly different versions of this protein that give them variable sensitivity to sourness. It may also open up new possibilities to engineer small molecules that blunt Otop1’s function. These molecules could be added into nutritious but unappetizing “lemons” to turn them into tasty and attractive “lemonade” in order to encourage people to eat healthier.

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Xiaomeng Han is a graduate student in the Harvard Ph.D. Program in Neuroscience. She uses electron microscopy to study neuronal connectivity.

For More Information:

• To learn more about taste receptor cells and the labelled line theory, please check out this video presentation from Khan Academy.
• To learn more details about taste perception, see this article.
• Here is an interview of scientists who conducted research on sour taste sensing from The Scientist magazine.
• A blog article about the discovery of Otop1 as the sour sensor protein can be found here.
• More information on how genetic different in taste sensors (receptors) influence our food preference can be found in this blog article.