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Analytical Chemistry

We Have the Touch

OK, let’s get reductionist, and let’s see why getting reductionist often works so well. How do you know when your finger has touched something? You feel it – but how do you feel it? Your nerves have sent an impulse to your brain, which interprets it as something having physically come into contact with your finger tip, but what sets off that impulse? Trace the sensory neurons all the way back and you will find them branching into small filament-like endings, working their way between the cells in the layers of the skin. It must be happening there. If you examine such tissue with a microscope, you come across all sorts of odd little structures – Meissner’s corpuscles, Ruffini’s end organs, Merkel’s discs and more – where those neurons end. All named after people who spent a great deal of time peering into microscopes, back when. And over the years it’s been shown that some of these are more sensitive to fast vibrations, some to slower ones, some to transient pressure and some to sustained, and so on. They are, in fact, like a keyboard instrument – you are carrying a vast microscopic alien piano around in the outer layers of your skin, although nothing could be less alien to you in reality.

But how do they work? What happens? When you get down to it, touch is indeed a physical sensation: those skin layers have moved, bowing inwards ever so slightly. All those sensory structures seem to feature layers of membranes around them, and those membranes have been compressed by a tiny bit and made to change their shapes. What else is touch, finally? Something about pushing those membranes out of shape in such a fashion makes them set off a signal down the rest of the nerve fiber, and every such signal is, in the end, a wave of chemical concentration.

Down further, down to the molecules. We know from still more decades of painstaking studies about receptor proteins, which sit in such membranes with part of their structure on the outside and part of it on the inside. Many of them respond to small molecules or protein ligands; they alter their shape when one of them binds. Transmembrane helices rebunch and slide over each other, as if you’d applied gripping pressure to a handful of slightly slippery marker pens and caused them to rearrange. The structures on the inner face of the membrane turn and expose fresh binding surfaces, attracting some partner proteins and releasing others, and some of these are catalytic: activity is unleashed to suddenly pulse out higher concentrations of some messenger (calcium ions, small phosphorylated molecules, what have you), which set off still more activity as they hit their own binding partners.

So what’s the “touch receptor” protein? And what sets it off when a membrane bends? That’s been studied, too – these proteins are named things like Piezo1 and Piezo2, and they do indeed sit in the cellular membrane and set off second-messenger signals as described. But how do they do it? What do they look like? What bends, and how? Well, now we know that, too. Papers have appeared over the last few years with partial structures, but thanks to some really impressive cryo-electron microscopy and separate studies of the proteins as they sit in small artificial lipid membranes, the picture is almost in focus. (Here’s a writeup in Nature).

 

The Piezo protein complexes are huge and they look like no other protein I’ve ever seen. They spread out in bent threefold symmetry, like a Sicilian trinacria or a three-armed barred spiral galaxy if such a thing existed, and each blade of this propeller-like structure has 38 of those transmembrane protein helices. There’s a view from the intracellular side at right, but what it doesn’t get across is that the whole is curved by the geometry of these helices into a bowl shape all of 28 nanometers wide. It’s open towards the outside of the membrane, where is a cap-like structure in the center, and in the very center of the whole thing there is a pore, where the shaft would fit if this thing were indeed a propeller.

And that pore is what does it. As these two papers show, the size of this whole complex is key, because it allows it to be extremely sensitive to flexing of the cell membrane. And that flexing could cause the ion-channel pore in the center to open and shut. There it is: the message heading into the neuron that something has happened. The second paper linked above actually reaches down with the tip of a AFM probe and pushes the center of the protein complex to demonstrate its springiness at just the sorts of pressures that it would experience on a cell surface. There’s still a chance that there is another accessory protein involved (not all the secrets have been revealed) but it may well be that it all comes down to those uncountable little membrane-imbedded Sicilian flag proteins, flexing and opening millions of times a minute as they sense the inflation of your lungs and the beating of your heart, as they respond to the pressure of the sidewalk under your feet, to the wind ruffling the shirt on your back, to the brush of fingertips as you walk past. Shake those hands.

22 comments on “We Have the Touch”

  1. Humble Scrivener says:

    Sapientia’s teeny, tiny, triskeliated Hero360 nib!

  2. Pp says:

    This is wonderful science. But none of the processes described are anything like the experience of the sensation on touch, and that is where reductionism fails.

    1. Peter S. Shenkin says:

      Reductionism isn’t about “experiencing” final effects. We do that just fine without any knowledge at all. Reductionism is about explaining final effects based on contributing components.

  3. Eugene says:

    Amazing evolved mechanical device. Calls to mind some of these devices, “Ortho-planar linear-motion springs” https://doi.org/10.1016/S0094-114X(01)00051-9

  4. Churlish says:

    Just a magnificent writeup Derrick, progressing from the sensation of touch to physiology and cell biology to the molecular level.

  5. loupgarous says:

    Good essay! I’ve always associated the triskelion with the Isle of Man flag, whose device is those same three flexed legs, but wearing armor and golden spurs. Of course, Sicily’s claim to the heraldry goes farther back, but any gear head knows the world’s deadliest motorcyle race is the Isle of Man Tourist Trophy.

    The certain winner in an butt-kicking contest, either way.

    https://upload.wikimedia.org/wikipedia/commons/thumb/5/5d/Flag_of_the_Isle_of_Mann.svg/1280px-Flag_of_the_Isle_of_Mann.svg.png

    1. Jon says:

      100 quatloos to you, sir.

    2. NJBiologist says:

      I would have gone with the coat of arms of Fuessen, Germany–but then, I’m biased. (A quick web search suggests they were using the motif by 1473; I don’t know how that compares.)

      1. Derek Lowe says:

        It’s on coins from Sicily in 300 BC, so they may have a priority claim (!)

        1. NJBiologist says:

          Yeah, I think you’re right. Fuessen itself only dates to the 1200s.

  6. Eugene says:

    Ortho-linear spring used in robotic fiber-optic tactile sensor, https://www.mdpi.com/1424-8220/17/10/2337/htm

  7. Barry says:

    Wonderful that it’s AFM that finally elucidates our touch receptors. To understand our own ability to get signal from a fingertip, we needed to build a touch-sensitive fingertip.

    1. Kelvin says:

      Indeed, very poetic, as is Derek’s post. Beautiful science, beautifully done, and beautifully explained!

      1. Kelvin says:

        PS. The AFM touching and feeling our own primary touch sensor actually made me think of Michelangelo’s painting in the Sistine Chapel.

        1. Anonymous says:

          Quick, send your idea to the authors for the journal’s cover page illustration!

        2. Anonymous says:

          I thought I’d post a link to some parody art work of “The Creation of Adam” on the Sistine Chapel but it turns out that there are now too many to count or link. Spiderman, Bart Simpson, Pizza, Kitten, … no chemistry or biology, so far. Just google “Creation of Adam Parody” or “Sistine Chapel Parody.”

  8. algorizmi says:

    Another triskelion protein is clathrin which can from a soccer ball quaternary structure.
    https://en.wikipedia.org/wiki/File:Clathrin_cage_viewed_by_croelectron_microscopy.jpg

  9. drsnowboard says:

    Pull my chin, stroke my hair, scratch my nose, hug my knees
    Try drink, food, cigarette, tension will not ease
    I tap my fingers, fold my arms, breathe in deep, cross my legs
    Shrug my shoulders, stretch my back, but nothing seems to please……

    Peter Gabriel methinks

    1. drsnowboard says:

      ah and you linked it… my bad

      1. Derek Lowe says:

        No problem! I’m glad someone recognized it before they clicked.

  10. Mike D. says:

    Hey, we used to use those things to let us play 45 RPM records on LP turntables!

  11. Paul Zhang says:

    I’m a junior high school student. In my sophomore I was avidly studying the PIEZO proteins because PIEZO2 had recently been implicated in the chronic pain condition tactile allodynia. I was hoping to harness computational modeling to (hand-wavily) develop an inhibitor of PIEZO2 and hopefully treat tactile allodynia (yeah, I know). I only found In The Pipeline late into my sophomore year, and looking back my approach was painfully naive, especially given a structure of PIEZO2 had not yet come out (until now!). Despite the project being essentially impossible, I was very excited by the existence and workings of such gigantic complicated proteins like PIEZO mediating something as complex as mechanosensation.

    So I was pleasantly surprised when Dr. Lowe published this blog post outlining advances in PIEZO(2) research. (:D) Thank you, Dr. Lowe, for writing In the Pipeline and this blog post specifically. It seems to me that a lot more excitement went this blog post than your usual fare, and I’m happy that others share my delight about PIEZO as well. Also, I think the PIEZO proteins bear an uncanny resemblance to fidget spinners, a funny toy whose popularity spiked a few years ago when I was in middle school. Pretty sure I made a meme about that some time ago.

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