Media’s talk of a ‘misery molecule’ is misleading

“Scientists have found the brain’s most miserable molecule,” according to The Sunday Times, which is apparently “the protein involved in all our feelings of stress, anxiety and even depression”.

It’s a great headline, but a hugely sweeping claim. This "misery molecule" story is actually based on a complex scientific study looking at the three-dimensional structure of a type of hormone receptor.

Hormone receptors are molecules found on the surface of cells that can bind to specific hormones. Once this binding occurs it can lead to changes in how the cells behave. The researchers were studying a receptor for a hormone called corticotrophin-releasing factor type 1 (CRF1).

CRF1 is thought to play a role in response to stress, and has been considered as a possible drug target for the treatment of depression and anxiety. Until now researchers had a poor understanding of the structure of the CRF1 receptor. This has made it difficult to design effective drugs to target the receptor.

In this study, the researchers used advanced – and extremely powerful – X-ray imaging techniques to get a detailed image of the atomic structure of the molecule.

With this information, researchers may be better able to create potential drug therapies blocking the effects of CRF1. These could potentially be useful in helping to relieve symptoms of stress, depression and anxiety. But research aiming to build on this information is still at a very early stage.

Where did the story come from?

The study was carried out by researchers from Heptares Therapeutics Ltd in the UK and was published in the peer-reviewed scientific journal, Nature. Heptares is a company that is developing new medicines to target hormone receptors. It recently issued a press release about the CRF1 research.

No sources of external funding are reported.

The Sunday Times and the Daily Mail have both overinterpreted the implications of this research. The aim of the study was to examine the structure of a particular type of protein receptor that previous work has suggested is involved in response to stress. They have not discovered a “misery molecule” and its role in stress, depression or anxiety was not directly investigated by this study.

These conditions are complex, and suggesting that there is one single “misery molecule” responsible for them all is a gross oversimplification.

What kind of research was this?

This was a laboratory study that looked at the structure of a particular type of molecule – a class B G-protein-coupled receptor (GPCR). GPCRs are positioned on the cell surface and transmit signals from hormones and other chemicals outside the cell into the cell.

Corticotropin-releasing factor (CRF) is a type of hormone that regulates the body’s response to stress. It is believed to be involved in a wide range of responses including appetite control, cardiovascular regulation, glucose breakdown, immune function and behaviour.

There are two types of CRF. CRF1 receptors are found in brain tissue in areas including the pituitary and hypothalamus that produce hormones that regulate the bodily functions. These receptors are part of a family of GPCRs.

Chemicals that block CRF1 receptors (CRF1 receptor antagonists) are believed to have potential as a way to treat stress-related conditions such as anxiety, depression and irritable bowel syndrome.

So far, structural information on class B GPCRs is limited to understanding only the end of the protein that sits outside of the cell. However, the part that could be a potential target for small molecular drugs – the part that spans the cell membrane – is not well understood. This part was dubbed “the crevice” by researchers (or in more technical terms – a transmembrane domain or TMD).

Researchers hope that understanding the structure of this “crevice” could one day help them in drug development.

What did the research involve?

The researchers produced CRF1 protein that lacked the part of the protein that sits outside of the cell and would not change structure due to heat. They then formed crystals of this protein, and examined them by using advanced methods based on targeting X-rays at the crystals and seeing how they were deflected by the crystals. This technique is called crystallography (a more primitive version of this technique was used in the discovery of DNA).

Computer programs used this data to determine the structure of the transmembrane part of the protein and produce images of it.

What were the basic results?

The researchers report complex structural detail of the transmembrane part of the CRF1 receptor, and show diagrams representing what it looks like. This included identifying which part of its structure interacts with a small molecule that blocks the action of the receptor (an antagonist) and so prevents any response from the cell.

How did the researchers interpret the results?

The researchers conclude that structure of the TMD of the CRF1 receptor “provides a model for all class B GPCRs and may aid in the design of new small-molecule drugs for diseases of brain and metabolism”.

They have studied how it interacts with a receptor blocker and say that to further their understanding of the mode of action of class B GPCRs, they now need to study the structure of the full receptor when bound with a molecule that triggers a response from the cell (an agonist) rather than prevents one.

Conclusion

This complex scientific study describes the structure of the transmembrane domain of the corticotropin-releasing factor receptor type 1 (CRF1). This receptor molecule is believed to be involved in response to stress, and has previously been considered as a possible drug target for the treatment of depression and anxiety. However, up until now researchers have had poor understanding of the structure of the part of this protein that crosses the cell membrane.

The researchers hope that the understanding they have gained as a result of this study will help them design small molecular drugs that could target this receptor and other related receptors.

This research may be of value on informing future drug development, but this research is in its very early stages.

A drug to block the effects of the so-called “misery molecule” is unlikely to be available anytime soon.