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The Proteins That Help Us Feel the World: Part 1

 •  • by Paul Ingraham
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Weekly nuggets of pain science news and insight, usually 100-300 words, with the occasional longer post. The blog is the “director’s commentary” on the core content of a library of major articles and books about common painful problems and popular treatments. See the blog archives or updates for the whole site.

How do physical stimuli turn into sensations? How exactly do we turn what’s around us into nerve impulses? “Transduction” is one of my favourite concepts in biology: the conversion of forces into electricity. We are all familiar with transduction in outline. For instance, we know that photons strike cells in our retina and trigger nerve impulses. But exactly how does that kind of thing work?

Some of these mechanisms remain unsolved mysteries of molecular biology, but others are now almost well understood. David Julius and Ardem Patapoutian just shared the Nobel for Medicine or Physiology for their discovery of proteins that transduce some basic stimuli into nerve impulses. It’s all dizzyingly complex, of course, but it can be oversimplified down to this: they enable us to detect heat, cold, and pressure.

And this all about pain, too. Because extremes of temperature and force are dangerous! So these proteins are also the most basic components of our alarm systems.

These discoveries are only about ten to twenty years old, and have been followed by many more like them, the dawn of a much more detailed science of sensation.

Proteins! How do they work?

The most specific explanation possible for most biological marvels is proteins. One way or another, it’s usually about the proteins. But how does a protein help us feel anything? Proteins are mind-bendingly complex little nanomachines, effectively black boxes with intricate clockwork-like guts we can barely comprehend. But we know some things about what they react to and how.

The Nobel proteins are “receptors,” embedded in cell membranes with their heads and antennae sticking out, and their tails on the inside. They are “pores” in the cell of the skin that can open or close. When exposed to the right stimulus, they warp and wiggle in an instant, opening a channel for a flood of ions (atoms with a charge). This why you can also call them “ion gates,” which sounds very sci-fi. If enough ion gates open at once, they triggers a nerve impulse — a signal about something happening around the cell, like “heat!” or “mechanical deformation!” or “Klingons on the starboard bow!”

Or “spice!”

Dr. David Julius versus the spice

The first of the Nobel proteins is often called the “capsaicin receptor,” because it reacts to the active ingredient in chili pepper. It was discovered by looking for the genes that cells need to make that receptor. His lab tested many genes, until they found one that could, when expressed in cultured cells, make them sensitive to capsaicin. It was 1997, and this was all much more difficult and tedious back then.

This protein’s true and full name is Transient Receptor Potential Cation Channel Subfamily V Member 1, or TRPV1 for short. And it doesn’t just respond to spice. It also responds to scalding heat — which is why “spicy” and “hot” are literally the same sensation, just with different significance. The day that was noticed, someone in that lab surely said, loudly, “Holy shit!” Probably all of them. That’s how scientists say “eureka” these days.

It’s weird and fun that this one receptor detects two kinds of heat.

And TRPV1 has more tricks up its intricately folded sleeve. It’s a gifted protein that also reacts to the active ingredients in mustard and wasabi, to acidic conditions, to inflammatory molecules, and to some cannabinoids, like anandamide (which is quite similar to THC). So what does TRPV1 do? Lots.

(Fun fact: capsaicin is a vallinoid, which is a cool word for a family of molecules related to, yes, that vanilla.)

A diagram of the structure of the TRPV1 protein, which contains about 800 amino acids. Imagine how many different ways there are to arrange a chain with 800 links. This is large for a protein in a human cell, but not the largest. The mean is 431 & the top of the scale is about a thousand (excluding a few freaks like titin at ~30,000).

A protein for every stimuli

Before the ink was dry on their original report, Dr. Julius and his team were already looking for a protein that transduces the feeling of a cool spring day — a cold receptor, a protein that lets the ions flow at a much lower temperature. Meanwhile, Ardem Patapoutian was doing the same thing! Both labs then independently and simultaneously discovered TRPM8, an ion gate opened by temperatures of 20˚C, give or take a few, instead of TRPV1’s 40˚C.

And there are still other proteins that open like flowers in different temperatures, each one covering a section of the thermometer. And the discoveries of TRPV1 and TRP8 triggered a research rush to identify other kinds of receptors. The basic mechanisms of touch were still unknown at the time, and especially tantalizing.

How does squishing tissue turn into the perception of pressure?

Papoutian’s team pursued this, earning the other half of the Nobel. Charmingly, they started out by identifying natural cells that were sensitive to touch by poking them, microscopically. I am not joking: they literally poked cells with a microscopic stick until they found ones that responded with a little “spark” of electricity.

They finally found that spark, and then they “just” had to identify the spark plug: the protein that was reacting to the poke. They found two: Piezo1 and Piezo2 were announced in 2010. And that is why Patapoutian is sharing a prize with Julius.

Piezo1 and Piezo2 use the force

Piezo1 and Piezo2 both react to the flexing of the cell membranes in which they are thickly embedded, like rhinestones on an Elvis impersonator. The deformation of the cell membrane is a microcosm of a thumb pressing into your skin, which bends the membranes of the nerve cells in the area, opening millions of Piezo1 and Piezo2 proteins, so that kajillions of ions can pass through them, triggering nerve impulses.

This is scientific reductionism at its most dazzling, revealing the exotic nano-scale engines that power familiar human experiences, the answer at the end of a chain of child’s “but why” questions.

The thumb bends the skin, flexing the membranes of every cell in the area. Proteins embedded in the cell membranes, Piezo1 & Piezo2, transduce the flexion into nerve impulses.

But they also power un-familiar human experiences! What we consciously feel thanks to the Piezo proteins is the tip of a mighty iceberg of subtle sensation. The biological power and utility of these engines is breathtaking. They are responsible not just for the pressure component of touch, but a truly staggering variety of other biological signals, from knowing when your bladder is full to the position of your limbs are in space to which direction your eyes are pointing.

Piezo1/2 are not just the engines of touch, they are also the engines of the greatly under-appreciated “sixth sense,” proprioception, the sense of position and movement. If all your Piezo receptors vanished, it would probably kill you in seconds or minutes — that’s how much your physiology depends on knowing when tissues are stretching, flexing, twisting, and compressing.

To be continued.

When I started this post, I sincerely thought it would be a short one, just a handful of paragraphs highlighting the relationship between this Nobel Prize and pain. Ha! Such adorable optimism! I fell down the rabbit hole, as I so often do. It was just so interesting! So here I am around a thousand words, and I’ve barely touched on the pain angle.

I continued with another post on Nov 26:

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