When we eat sour food, we instantaneously react due to a taste-sensing circuit between the tongue and the brain. Two papers published today (September 19)—one in Cell and the other in Current Biology—show that the otopetrin-1 proton channel in the tongue’s sour taste receptors is one of the components responsible for sour taste sensing in mice.
These findings add to the body of sour taste research “from the molecular level, of how these protons are transported, up to the level of how the mice are able to taste it,” says Lucie Delemotte, a computational biophysicist at KTH Royal Institute of Technology who was not involved with either study.
On the tongue, each taste bud contains a cluster of taste receptor cells innervated by a gustatory nerve network. The tips of these cells have a variety of taste molecule-capturing proteins and, in the case of sour detection, proteins that are called proton channels that sense pH.
A team led by Charles Zuker at Columbia University Medical Center identified a potential sour taste receptor for the first time in 2006, and he and other researchers have continued to work on clarifying the mechanics and function of that receptor along with other possible sour taste receptors. A breakthrough occurred last year when Emily Liman of the University of Southern California’s lab discovered that otopetrin-1 (also referred to as OTOP1) was a proton channel also implicated in detecting sour tastes. But the researchers stopped short of demonstrating that OTOP1 was required for sour taste sensing in an actual animal—until now.
“[OTOP1] clearly was a proton channel. It could sense pH and confer sensitivity to pH. But did it do that in the context of an animal? That’s what Zuker’s paper in Cell and our paper in Current Biology both address,” says Liman.
The OTOP1 gene had previously been shown to be required for the formation of otoconia, calcium carbonate crystals in the inner ear that allow us to respond to gravity and acceleration. There was no indication that it would have anything to do with sour taste, says Liman. “It seemed highly unlikely. Why would a gene that’s expressed in your ear function in your tongue as the sour receptor?” she says. “This was one of the last genes that we tested.”
Zuker’s team developed two strains of mice for their experiments: a mouse with a nonfunctioning gene that encodes OTOP1 and a mouse with sweet taste receptor cells that have OTOP-1 channels. They gave the mice acidic liquids to drink and observed the animals’ behavioral preferences and cellular responses at the taste receptor level.
“When we knock out OTOP1, we see that the sour taste receptor cells no longer respond to the acid stimuli. And in the knock-in animal, where we express the sour receptor OTOP1 in the sweet cells, now the sweet cells also respond to sour,” says Jin Zhang, a postdoc in Zuker’s lab and the first author of the Cell paper.
Although Zuker's and Liman’s groups worked independently, the two studies have some similarity in setup and findings. Liman’s lab also used a knockout mouse to understand the function of OTOP1 on gustatory nerves, which are located in taste buds. “Both labs found that the gustatory nerve response to acids was severely attenuated, indicating that OTOP1 function is required for the gustatory response to sour,” Liman tells The Scientist.
Liman’s lab also determined that the OTOP1 receptor is needed for protons to enter taste receptor cells. “When something is acidic, it has a high concentration of protons, so it makes sense that a molecule like that could serve as a sensor for pH,” says Liman.
Meanwhile, Zuker’s lab looked at the responses of ganglion neurons that go between the taste buds and the brainstem. “We found that sour uses its own dedicated circuit to convey its signal from the peripheral to the brain. We also identified the neurons responsible for transmitting the sour signal in the taste ganglia and in the brainstem. When we activate the sour-responding neurons in the brainstem when animals are drinking water, animals behave as if they are drinking sour solutions,” says Zhang.
Two other otopetrin proton channels are known to exist: OTOP2 and OTOP3. The function of those is currently unknown, says Delemotte. “Biophysically, it’s known that they have similar characteristics to OTOP1, but it’s not understood what functions they have physiologically,” she tells The Scientist.
Future research in each lab involves connecting what the researchers know about sour and other tastes in the tongue to different parts of the brain. “We see how it’s using dedicated circuits from the tongue to the brainstem, but how about from the brainstem to the cortex? There are a lot of interesting questions following up on this,” says Zhang.
Understanding the pathway between taste receptors and the brain will give insight into the evolution of behavioral reactions to different tastes. “For example, most animals will find bitter innately aversive and sweet innately attractive. By identifying the cell types at each stage in the brain, we can start to understand how complex behaviors are generated,” says Liman.
Emily Makowski is an intern at The Scientist. Email her at firstname.lastname@example.org.