Sours are all the rage these days in the craft beer world—those puckery, funky tastes have struck a note with certain drinkers. Moreover, when mixed with the right amount of counterbalancing sweet flavor, sour flavoring produced a patch of candies that were part of many kids taste profile while growing up. Among the five basic tastes—the others being bitter, sweet, salty, and umami—it is arguably the most subtle. In small amounts, it adds a critical tang to an otherwise bland dish. At higher concentrations and on its own, it’s unpleasant or even painful. Yet, for many the sensation of sour is enjoyed and even desired, but what initiates those feelings? Well, University of Southern California (USC) scientists may have vaulted the first hurdle and solved a mystery: how sour tastes are sensed by animals.

Reporting in the latest issue of Current Biology through an article titled “Cellular and Neural Responses to Sour Stimuli Require the Proton Channel Otop1,” researchers found that a sensor for pH on the tongue is the otopetrin 1 gene (Otop1). Otop1 is a member of a class of molecules called ion channels, which allow charged ions to cross cell membranes. In the case of Otop1, the charged ion carried across the membrane is H+, which is released into the mouth by acids.

“We showed that the ion channel Otopetrin-1, a proton-selective channel normally involved in the sensation of gravity in the vestibular system, is essential for sour sensing in the taste system,” the authors wrote.

Last year, the same research team published findings in Science that closed in on the sour-taste sensor. In that study, the investigators used high-throughput sequencing methods made possible by advances in genomics to identify a list of roughly 40 previously uncharacterized genes that could encode a sour sensor. By studying the function of each gene, they whittled the list down to Otop1 because it was the only candidate that, when introduced into non-taste cells, gave them the ability to respond to acids.

While the USC scientists had identified OTOP1—the protein encoded by the Otop1 gene—as forming a proton channel, they did not show that it was required for sour-taste responses in an intact animal.

Taste occurs when ingested chemicals interact with specialized cells on the tongue and palate. These cells are called taste receptor cells and are found in taste buds, which are concentrated on the back, sides, and front of the tongue and on the roof of the mouth. Different taste receptor cells respond to each of the five basic tastes, and they release neurotransmitters onto gustatory nerves that send signals to the brain. This allows the nervous system to determine whether the ingested chemical has qualities perceived as bitter, sweet, umami, sour, salty, or a mix of the five.

[Teng et al., Cellular and Neural Responses to Sour Stimuli Require the Proton Channel Otop1, Current Biology (2019)]

This new study followed up on previous findings that OTOP1 gave cells the ability to detect low pH. The research team employed gene-editing technology to generate mice with an inactivated Otop1 gene to test if the OTOP1 protein was necessary for responding to sour chemicals—or acids. When sour taste receptor cells are exposed to acids, they respond by producing an electrical signal—or current—because of the movement of H+ ions across the cell’s membrane.

“We demonstrated that knockout of Otop1 eliminates acid responses from sour-sensing taste receptor cells (TRCs), the authors noted. “In addition, we show that mice engineered to express otopetrin-1 in sweet TRCs have sweet cells that also respond to sour stimuli. Next, we genetically identified the taste ganglion neurons mediating each of the five basic taste qualities and demonstrate that sour taste uses its own dedicated labeled line from TRCs in the tongue to finely tuned taste neurons in the brain to trigger aversive behaviors.”

The researchers also showed that the sour taste receptor cells from the mice with nonfunctional OTOP1 did not have detectable currents representing the movement of H+ into cells. The sour taste receptor cells from the mutant mice also did not decrease their intracellular pH when exposed to acids, which would happen if H+ ions moved into the cell. Finally, the sour taste receptor cells from the mutant mice did not produce action potentials—another electrical signal—which is needed to activate the gustatory nerve and signal to the brain in response to some acidic solutions.

Whereas the previous experiments were performed with isolated taste receptor cells, the researchers also studied the importance of OTOP1 in mice by measuring the activity of the gustatory nerves in response to sour-tasting solutions introduced into the mouth of the mice. For these experiments, they teamed up with researchers at the University of Colorado Medical School. As expected, the activity of these nerves was severely reduced in mice with nonfunctional OTOP1, showing that the ability of the mice to sense acidic solutions—and thus sour tastes—was impaired.

“Our results show that OTOP1 is a bona fide sour taste receptor,” explained senior study author Emily Liman, PhD, professor of biological sciences at USC. “This is the first definitive evidence for a protein that is both necessary and sufficient for sour taste receptor cells to respond to acids and stimulate the nerves to enable sour taste perception.”

Surprisingly, the scientists found that mice with a nonfunctional Otop1 gene could still produce a small response to sour taste stimuli; the sour taste receptor cells still produced a few action potentials and the gustatory nerve produced a small response to very acidic stimuli. They postulate that another signaling mechanism, unrelated to OTOP1, also contributes to sour taste. They also tested the behavior in mice and found that the mice with a nonfunctional Otop1 gene still found acidic stimuli aversive.

“The behavioral response to acidic stimuli that are ingested is complex. You have the taste receptor cells that can detect acids, but you also have the pain system, which responds to low pH,” Liman concluded. “Finding the molecular basis for the sour taste sensor takes us one step closer to understanding how different animals and individuals perceive the world.”

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