The “orphan” that’s linked to stress, anxiety, and depression
Mental Health Depression Anxiety

The “orphan” that’s linked to stress, anxiety, and depression

Dr. Feriha Fatima Khidri
Dr. Feriha Fatima Khidri

In 10 seconds? Scientists have discovered that depression and anxiety are linked to a receptor located in our brain. The finding may pave the way for novel approaches and therapies to “switch off” major depressive and mood disorders.

Isn’t that great? So how did scientists discover it? Researchers determined the structure of a depression-inked receptor, GPR158 in the human brain using a technique known as single-particle cryo-electron microscopy (cryo-EM).

Wait, don’t blind me with science, what is GPR158? It is an orphan G protein-coupled receptor (GPCR) highly expressed in the brain, where it controls synapse formation and function. Synapses are junctions in our brains through which the fundamental units of the brain – neurons send signals to each other – and these signals play a key role in our moods and emotions. This process – neurotransmission – could not happen without receptors, which are proteins that can bind to or ‘receive’ the neurochemical – the message - sent from one brain cell to another via the synapse.

OK, and then what? Why is this ‘receptor’ called an “orphan”? GPR158 has come to the attention of researchers since it was found to be involved in the physiological responses to stress and depression, cognition, memory, and mood. However, its structural organization and mechanisms were not well understood; because of this they named it an “orphan receptor.”

Let's learn more about how our emotions are managed. Genes and the environment both affect how people show emotional reactions to stress. Most responses to stress are adaptive changes that help maintain normal mental and physical functioning, but when they go wrong, they can cause disordered behavior that can lead to major depressive disorders. It is well known that the medial prefrontal cortex - a part of the brain - plays a key role in controlling mood and GPR158 can be abundant when someone is in a depressed state. Abnormalities in the morphology or function of this part of the brain may contribute to stress, anxiety, or depression.

So, I know the spot where my anxiety levels are shooting up… But what’s the discovery? In the recent study, scientists discovered the structure of the human GPR158. This protein is closely associated in the brain with a sort of "on and off switch for signals" the so-called G protein signaling complex (RGS). Without going into too many details, the insight into the structure of this depression-linked GDR158 receptor offers a way for drug developers to develop tiny molecules that de-activate it by targeting certain parts of it  - offering hope to treat depression in a novel way. The discovery was made in many ways thanks to cryo-EM microscopes that employ an electron beam to visualize protein assemblies at near-atomic resolution.

The structures of GPR158 discovered by cryo-electron microscopy. The "cached domain" in to can be the target for drugs to "swithch off" depression and anxiety.

Do past studies back this up? Why is the discovery significant? In animal models, anxiety and depression are linked to a lack of regulation in the medial prefrontal cortex. Symptoms can be relieved by medicines that work on this part of the brain. Most theories agree that chemical messengers in your body, called neurotransmitters, are linked to severe depression. Even though these neurotransmitters have been the focus of therapy in the past, their efficacy is limited. In the past, traditional antidepressant treatment was shown to have strong negative effects on some people, take a long time to kick in for certain individuals, or not work at all for some people with depression. This has left a need for new approaches.

So what’s the link between the orphan receptor and depression? The GPR158 acts as a novel regulator in the prefrontal cortex. This receptor shows increased activity in the brain of an individual with major depressive disorder. When scientists exposed mice to chronic stress, they found elevated GPR158 protein levels in the brain; and, when this protein was experimentally increased, depressive-like behaviors were observed. Now here comes the fascinating thing! When scientists ablated GPR158, they found antidepressant-like symptoms and stress resiliency. So, that’s how a new player in mood regulation has been uncovered, offering a pharmacological target for managing clinicaldepression, stress, and anxiety. We don’t want to switch off “useful” stress or anxiety after all that, for example ,can protect you from physical harm!

Why are certain people  resistant to depression?

Well, you might know certain people in your family or friends, who either cope well with pressure or the opposite.

A friend might be not too worried about failing her exam while another might get depressed when she 'only' gets into the top 3 but doesn't get the first place.

Can we link this to genetically lacking the GPR158 receptor that makes an individual resist depression? Pharmacological experiments have shown that the loss of GPR158 exerts antidepressant-like effects.

So, the next goal is to come up with a drug that can target this receptor and possibly put an end to anxiety, stress, and depression - it is a promising discovery but getting to an approved drug is a long journey taking several years.

Feriha has distilled 8 research papers, saving you 28 hours of reading time.

The Science Integrity Check of this 3-min Science Digest was performed by Dr. Ángel V. Jiménez.

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