Finding the misery molecule? More like imaging a candidate


Depression, like just about every other mental disease, is a strange and mysterious beast. We’ve reached the stage where most people finally understand that it’s really an illness, really a physical problem, not something can be controlled. We know that there are myriad drugs that can help: citalopram, sertraline, paroxetine, fluoxetine…  But we still can’t reach out and touch it. We still can’t predict it. There’s still not a physical test that you can do. An assay that proves that no, this person isn’t just lazy or melancholy or antisocial: they are depressed.

The headlines

Over the weekend, the news outlets got a bit excited at the prospect that scientists had finally discovered “the molecule responsible for causing feelings of depression” (Independent), “the brain’s most miserable molecule” (The Sunday Times) “the little bastard molecule that causes depression” (msn), “The Thing Responsible for Depression” (Jezebel).

And the science

I wish I could say I’m as excited as they are, but of course the science is never as simple as this. The actual paper released is a slog to say the least, and more Physics than Biology, but I’ll give it a go. 

A hormone receptor 

There are a series of receptors called GPCRs. These carry signals from other molecules like hormones across the membranes of cells. There are four different types of GPCR receptor labelled A-C and frizzled. (Yes, frizzled!!) The B class (known as secretins) is split into another two sub classes: secretins (yes, I know that’s the name of the whole class too, don’t blame me) and adhesion receptors. The secretin subfamily has 15 receptors in it and those receptors are drug targets for just about every major disease you can think of. Diabetes, osteoporosis, migraine and … depression and anxiety. There are lots of ways to influence those receptors, but what nobody has found yet are “small-molecule modulators” of these receptors. Essentially, nobody has yet created a drug that can change the way that they work. 

While there has been lots of successful work on the A class of GPCRs, work on the B class has been more limited. The limited amount of previous work that has been done has concentrated on the part of the receptor outside the cell (the extracellular domain or ECD) rather than the part that goes through the membrane of the cell.

A stress hormone

There is a hormone called corticotropin-releasing factor (CRF) also known as corticotropin-releasing hormone (CRH) that is known to play a role in tonnes of things including stress responses and appetites. It has a receptor called CRF1RThe scientists who wrote this paper believe that CRF interacts with the transmembrane domain (TMD) of this receptor, and so they have identified its 3D structure using the synchotron, Diamond, (which is sort of like X-ray imaging. I think of it as a huge snazzy laser, but closetphysicist tells me this is completely inaccurate). This is important both because of its implications for that particular receptor, and because it can also serve as a model for other class B GPCRs. 

Ribbon representation of CRF1R in rainbow colouration (amino terminus, blue; carboxy terminus, red) viewed from the membrane from two angles. The antagonist CP-376395 is depicted in space fill representation with carbon, nitrogen and oxygen atoms coloured magenta, blue and red, respectively. The disulphide bond linking ECL1 and TM3 is shown as yellow sticks. The thermostabilizing mutations are rendered as green sticks. The position of the T4L insertion is indicated.

Hollenstein et al (2013), Nature. This is what CRF1R looks like! (But go to http://www.nature.com/nature/journal/vaop/ncurrent/full/nature12357.html for the full original caption

And what does it mean?

The information from the study may make it easier for scientists to figure out how to make useful drugs that can target the receptor, and that could have implications for new antidepressants… in 10 years’ time or so. But actually it’s even less applied than that, because the role of CRF in depression and anxiety hasn’t even been fully investigated yet. This wasn’t a medical paper, in that it didn’t actually involve any patients or examination of what CRF or its receptor mean for people with depression.

So while it’s pretty interesting science, and could one day have some major implications, the newspapers really are over-egging this one a bit. The context and particular application of this science make it interesting – but this paper doesn’t even try to demonstrate a link between CRF1 and depression, never mind identifying one!

______________________________________________
K Hollenstein, J Kean, A Bortolato et al (2013) Nature
“Structure of class B GPCR corticotropin-releasing factor receptor 1”
doi:10.1038/nature12357

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2 responses to “Finding the misery molecule? More like imaging a candidate

  1. Erik Andrulis

    I’m with you on this one. I didn’t see the paper, so I’m glad you listed it here. If it’s ok with you, I’m going to link your article to the bottom of my blog post. If you’re interested, my post (not dissimilar to yours in skepticism) is here:

    http://erikandrulis.wordpress.com/2013/07/22/the-great-emptiness-and-the-promise-of-a-molecular-solution/

  2. Pingback: The Great Emptiness and the Promise of a Molecular Solution | Anacephalaeosis

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