Why You Always Know Where Your Nose Is

Often considered a sixth sense, proprioception is much less understood than the other five—researchers have identified molecules related to taste and smell, for example, but research on proprioception has lagged behind.

But it’s finally catching up. In a study recently published in the journal Nature, Woo and her colleagues from Scripps, Columbia University, and San Jose State University identified the key molecule that governs proprioception: the protein Piezo2, found in the membranes of special nerve cells in our muscles and tendons called proprioceptors.

When we move, our muscles and tendons get stretched, which puts tension on the proprioceptors’ membranes, explained Jorg Grandl, a Duke University neurobiologist unaffiliated with the study. That tension distorts each Piezo2 protein and causes a tunnel to open in its center. Small activating particles rush through the tunnel into the proprioceptor cell, causing it to fire an electrical impulse up the limb, through the spinal cord, to the brain. The whole process happens in a matter of milliseconds.

When Woo and her team deleted the Piezo2 gene from the proprioceptors in mice, the animals showed no body awareness. “The behavioral deficits are so striking,” she said: The mice would splay their legs outward in abnormal positions, sometimes even reaching them up into the air rather than toward the ground. When they walked, their bellies dragged as they doggy-paddled across the ground.

The study authors also dissected another group of mice to verify that the proprioceptors were actually the things detecting tension. Finding these skinny cells was relatively easy: The researchers had genetically modified these mice so that their proprioceptors glow a fluorescent red. After removing the cells from the body and placing them in a culture, Woo and her colleagues poked them with dull glass probes and measured the resulting electrical impulses. As they predicted, the impulse had a signature Piezo2-triggered pattern. Even when they removed the entire leg muscle, proprioceptors and all, and stitched the end of it to a post, tugging on the muscle yielded the same pattern. Only proprioceptors from mice without Piezo2 failed to respond to pokes and tugs.

Piezo2 doesn’t just detect forces in our proprioceptors—past research has also examined its role in the touch sensors of our skin, and even in our cartilage. Wolfgang Liedtke, a neurologist at Duke, studies how cartilage cells in our joints detect pressure and grow in response. Though scientists still don’t fully understand how it happens, Liedtke did find that when cartilage cells experience high pressure, like in a knee joint bearing weight, their Piezo2 proteins and other associated proteins also open and let in signaling particles. (Hence the name of the protein: “piesi” means “pressure” in Greek.)

For some people, especially the obese, this pressure means Piezo2 spends too much of the time pressed open, which causes cartilage cells to die and leads to arthritis. But Liedtke has found an interesting medical solution: A compound in tarantula venom, a non-toxic drug called GsMTx4, can stop cartilage damage by inactivating Piezo2 and its associates.

Though they share a key protein, pressure-sensing cartilage cells are distinct from propioreceptors, in that they only work within the cartilage itself. Proprioceptors, on the other hand, send signals to the brain, allowing us to perceive what they detect.

And this latest insight into how these cells work paints a much more nuanced picture of what a “sense” can be. Piezo proteins are only one sub-class in a very large array of proteins that help us detect things like temperature, blood pressure, even concentrations of chemicals in the blood, and it remains unclear just how many of these provide us with a unique sense. But one thing’s for certain—smell, taste, and company are only part of a larger picture.