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The Great Untangling

Here’s a family of proteins that people don’t encounter all that often, but they illustrate how odd and complicated human biology gets to be. The TRP (transient receptor potential) ion channels are a large family (28 members) divided into several groups. Many of them (although not all of them) are involved in sending sensory information to the brain, and it’s interesting to think about their variety and how they manage that.

Not to get too philosophical, but all our physical sensations from the outside world have to be mediated by some sort of receptor in our own bodies. Heat, cold, pressure, pain, pleasure – these are all constructs of our mental processing, but they (generally!) have physical referents. Our sensation of eyesight, for example, is a mental construct, with rather large and specially formed brain regions dedicated to it, but these layers of neurons are responding to impulses coming up the optic nerve, which in turn are set off by the receptors in the retina and their behavior when various wavelength of light hit them. Going further, those rhodopsin receptors are changing shape as retinal molecules isomerize when light hits them – vision comes down to a cis/trans double bond switch; that the spring from which everything flows, the first domino in the mighty chain.

The same goes for all our other physical sensations. The TRPV family of ion channels, for example, is what mediates the taste sensations of garlic and hot peppers, and contribute (as you’d figure) to feelings of heat and pain. The TRPM family is all over the place, but TRPM8 is responsible for the sensation of cold (and for the “cool” sensation of menthol, eucapyltol, and other compounds). In the same way that rhodopsin is balanced on a knife edge, to be tipped over by light hitting it, TRPM8 is similarly balanced so that its conformation changes as the temperature drops, which sets off changes in calcium flux and further messages inside the cells where it’s expressed. (TRPM3 in that same family is also a contributor to pain and inflammatory sensation). Meanwhile, the TRPA receptor (only one member in the family) is believed to be the mechanical stress mediator, responding to physical pressure. It’s something of a mystery, though, and other roles (in cold sensing, for example) have also been proposed. Confusingly, it also responds to pungent compounds (allicin from garlic) and to minty/cooling things like methyl salicylate.

OK, so a general picture would seem to be emerging – it’s tempting to go through the rest of the TRP channels and look for what sensations they’re associated with. But there’s where you run into the complications. To pick another family, there are six TRPC channels, and they seem to have nothing much to do with sensations. They’re found all through the brain, heart, and other tissues, and have cellular roles in normal function and disease that are still being teased out. Some of them are definitely involved in cardiomyopathies of various kinds, so there might be a link to sensing of mechanical stimulation of heart tissue, but that’s still not clear. What’s going on the in the brain with them is still very much open for debate, but the complex localization of the various subtypes tell us that there’s something important there, even if we have only vague ideas about what it might be.

Even the families that do have sensory roles have a lot of other things going on. Looking at human mutations tells you that there are layers of complexity – for example, mutations in that TRPM3 receptor, mentioned above, are associated with respiratory disease and inherited glaucoma, which is a long way from pain sensation. This family also has members like TRPM6 and TRPM7, which is involved in magnesium handling (reabsorption in the gut and other tissues), and probably cell adhesion behavior, perhaps through that pathway and perhaps not. And if you can figure out what TRPM2 is doing, you’re ahead of the rest of the research world, because it has not-well-worked-out roles in the brain, immune system, and metabolic functions. When the same protein has been linked to bipolar disorder, amyloid toxicity, TNF-alpha response, and insulin secretion, you know you’re in for a rough time.

Likewise, one of the TRPP group is probably involved in sour taste perception, but many of the others have been shown to lead to polycystic kidney disorders when mutated. And some of the other TRPPs, frankly, seem to be pretty much of unknown function – they’re out there, but we really don’t know why, or what happens when they’re altered. They don’t seem to be in the kidney disease area, and they don’t have any known sensory functions, but they’re presumably not being expressed in specific tissues just for the hell of it, either.

So this area would be a good example to bring up when it’s time to talk about how complex human biology gets, and how much we don’t know about it. Everything from “I feel cold” or “Boy, that’s a spicy Thai curry” to a whole list of serious diseases is tied together, in ways that are only partly understood, and which are obscured by big piles of functionality that we don’t know anything about at all. It also gives you a look at the whole “evolution is a tinkerer” aspect, in the way that these same protein motifs have been hijacked, diverted, repurposed and reused so many times over the last billion years. If evolution has a motto, it’s “Hey, man, whatever works”, and this is what you get after piling up unimaginable eons of that. It is a mess, a literally inhuman (nonhuman, ahuman) mess, and the untangling has just barely begun.

16 comments on “The Great Untangling”

  1. Anon says:

    Any of these TRP’s respond to emotions driven by chemical signals, perhaps?

    Or maybe even sickness and chemical imbalance in general.

  2. Peter Ellis says:

    This feels rather like trying to work out the function of glass tubing by seeing which bits of machinery stop working when you remove all tubing of a given gauge from a laboratory.

    Fundamentally, the function of a given TRPM gene isn’t “respond to sensation X”, it’s more like “provide a controllable means of getting ions from A to B”.

  3. tlp says:

    The more I learn about human biology, the more I feel like the whole notion of ‘function’ is a completely artificial concept. Yes it gives us perception as if we understand something and sometimes it even leads to some useful discoveries but at the level of evolution it’s completely meaningless.
    There are two opposite approaches to deal with it: either to accept that we’ll never understand evolution’s ‘logic’ and live happily with it, or to ditch evolution completely and create our own life, which we will understand. With the latest discoveries (CRISPR-Cas9 technology) it’s obvious where humanity is heading.

    1. DrOcto says:

      Interesting angle.

      You can’t get cancer if your genes can’t mutate because they were designed not to ever mutate.

      But can an engineered lifeform (in our image) be considered human? Consider itself human? Would it consider humans a threat?

      1. tlp says:

        If you manage to prevent gene mutation completely you probably won’t get cancer and also won’t get a chance to evolve (i.e. won’t get any beneficial mutations). But humans already have much faster ways to ‘adapt’ to extreme conditions (e.g. open space) by building protecting suites and defend themselves with weapons rather than relying on slow genetic tinkering. So why not freeze the genetic diversity as it is right now? You don’t have to develop whole new life, just prevent it from being ever changing.

        Disclaimer; I’m not really supporting the idea, I just like to think about it as an extremum where genetic engineering could take us.

  4. Patrick says:

    There are even TRPV1 channels in the CNS…

    It’s involved in reward amongst other things; see for example Nguyen et al., Transient Receptor Potential Vanilloid Type 1 Channel May Modulate Opioid Reward, Neuropsychopharmacology 39: 2414-2422
    PDF at http://www.nature.com/npp/journal/v39/n10/pdf/npp201490a.pdf

    Considering that capsaicin apparently crosses the BBB when given IP, I’m actually wondering whether this is part of the reason why spicy food is enjoyable – that capsaicin itself is psychoactive.

  5. Petros says:

    And huge efforts have been thrown at TRPV1 modulation with no progress but a string of clinical values

    1. Derek Lowe says:

      Yes indeed, part of the great ocean of money that has been poured into non-opiod pain pathways. . .

    2. Lars says:

      I thought this was because nonselective TRPV1 antagonists caused hyperthermia? Apparently there are several modes of activation for that receptor, and it’s been worked on since that result became known. I’m not sure what the state of the art is. Also, there is this: http://journals.lww.com/em-news/blog/BreakingNews/Pages/post.aspx?PostID=183

  6. jbosch says:

    Did you go to the same event as I did yesterday in Boston?

    1. Derek Lowe says:

      Nope, just coincidence, I guess (!)

  7. Chris Phoenix says:

    https://xkcd.com/1605/

    An illustration of your last paragraph, written especially for computer programmers who say “But this biology stuff is just software! How hard can it be?”

  8. UKPI says:

    Another layer of complexity of TRP channel signalling is based on the fact that a functional TRP channel is composed of 4 subnits, and that these functional tetramers can be homomeric or heteromeric (potentially even including non-TRP proteins). Homomers and heteromers can have different localisation, function, ion permeability, stimuli and signalling outputs, etc, and it is not always known which tetramers are most abundant/relevant in certain cell types.

    For this reason, this is also a clear example of a field where knockdown/-out and overexpression of the protein of intereste can give completely the wrong results because of changes in stoichiometry of channel subunits.

    1. UKPI says:

      Bad phrasing: with ‘wrong results’ (do they exist?) I of course meant ‘unexpected results that do not necessarily help answer the question that you hoped to address’…

  9. Lane Simonian says:

    Transient receptor potential ion channels can contribute to oxidative stress and to inflammation, pain, and a variety of diseases.

    https://www.ncbi.nlm.nih.gov/pubmed/21290315

    However, several agonists of these receptors such as capsaicin and eugenol are also antioxidants and may counteract the effects of receptor activation.

    http://www.nature.com/nm/journal/v19/n1/full/nm.3019.html

    http://www.eurekaselect.com/55068/article/effects-eugenol-central-nervous-system-its-possible-application-treatment-alzheimers

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645550/

  10. GutDecipher says:

    Was thinking a lot about TRPA1/TRPV1 a couple months ago when I got some szechuan peppercorns from my labmate and wanted to learn about hydroxy-alpha sanshool. Read a bunch of papers, started to write a blog post about it, then the papers started to contradict and negate each other, the KCNK family was dragged in, and at that point I was up to 700 words and exhaustedly I tabled the post. May go back to it at some point because the mechanosensation of taste is really fascinating to me, as are the transient covalent inhibition of these receptors.

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