Proteins offer window to pain

Our sense of touch helps to define our sense of self. If you can't feel a limb, it can seem a foreign object. I was recently listening to one woman explain how she lost feeling in her arm while asleep and when she woke up, she thought a snake had crawled into bed with her. She leapt from her bed beating at the unrecognized limb.

Understanding our senses has been a long term goal of science dating back hundreds of years. We have a fairly good understanding of sight and how molecular interactions in rods and cones result in the generation of nerve impulses to the brain. We have some understanding of how these impulses are mapped within our occipital lobes. There is even research being conducted into the development of bionic eyes, albeit not as sophisticated as the one used by the Six Million Dollar man.

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We have an appreciation of our sense of taste and smell which are essentially the same thing. The physical nature of molecular docking and conformational changes in receptor proteins is reasonably well understood in our taste buds and nasal cells. The response to chemicals in our environment - called chemitaxis - is arguably the oldest of all senses. Moving towards sugars, fats and proteins is an essential action for even the simplest cells as is moving away from acids, alkalis and other potentially harmful substances.

But touch has been a much more elusive sense to track down. In part, it is because touch is not as singular as sight or taste. There are multiple levels of touch - from the delicate detection of moving air molecules within the ear to the sensation of a gentle breeze across the back of the neck to the painful sensation of walking into an unseen street lamp. Perhaps not surprisingly, neuroanatomists have found multiple types of touch receptors embedded within our skin and throughout the body.

Indeed, our internal sense of touch is equally important to our sense of self as our external sense. If you close your eyes for a moment and move your hand, you have a reasonable sense of where it is in relation to your body. You could likely reach out for, say, a cup of coffee and while you might not be able to pick it up smoothly, you would at least have a sense of where your hand is in relation to the cup.

This sense of our body's position in space is a crucial ability called proprioception. It allows us to walk, reach, and do many other things since we have a sense of where our body is at any moment. When we lose connection with parts of our body, we can wake up thinking we are in bed with a snake because we don't know what the thing we are feeling is.

In 2013, one teenager girl arrived at a hospital in Calgary with an inability to hold her limbs still. Even if she tried hard to hold her arms and hands steady, her fingers would wiggle. If she closed her eyes, everything got worse. It appeared as though she lacked control over her limbs - a lack of proprioception.

When her doctors sequenced her DNA, they found mutations in a gene called PIEZO2. Just a few years earlier, researchers had discovered that this gene encoded for a pressure-sensitive protein critical to the sense of touch. The discovery of the gene and its related protein, along with a related protein called PIEZO1, were the high points in a decade long search to understand touch.

The proteins are ion channels and have an unusual shape. They are a trimeric system consisting of three arms branching out from a central pore, as determined by cryo-electron microscopy. The arms are laced into the cell membrane, woven in and out multiple times, with the result that the whole structure creates something of a dimple, a sort of daisy-like structure but with only three symmetrically place petals.

How the structure works is still a work in progress. One theory is that pressure on the cell causes the cytoplasm to push on the dimple, effectively 'popping' it outwards and resulting in a flat surface. The change in structure forces open the hole in the middle and allows the free flow of ions which generate the signal. While this is the simplest mechanism, it is also possible the blades of the protein are twisted by shifts in the cellular membrane. In this case, spinning outwards or inwards would control the opening.

The ongoing investigation into the structure of the protein is hampered by its large size - about five times the size of a typical protein - and an inability to develop model systems. But successful research on the PIEZO proteins may go a long way to helping us control pain.

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