Can you remember brushing your teeth this morning? Many people struggle to remember because it has become a subconscious habit for them.
Habits form who we are, from our morning routine to our patterns of speech and behaviour. They become so instinctual that we often forget that we’re even doing them. However, some habits can become harmful and negatively affect our lives. For instance, trichotillomania, which is a mental health condition in which someone has an instinctive urge to pull out their own hair � a behaviour that can cause distress and social anxiety.
Our mental health is a result of a complex interplay between environmental and biological factors. This month, we are highlighting the role of proteins in the development of mental health conditions. One such protein is the Serotonin Receptor, 5-HT1A, which is a critical component in the regulation of brain function.
Serotonin is a small-molecule neurotransmitter that is used to relay chemical messages throughout the brain and central nervous system. It has a variety of roles, including in regulating mood, behaviour, and learning. When a neuron is stimulated by nerve impulses, serotonin is released at the ends of the neuron. The released serotonin then binds to protein receptors on the next neuron in the sequence, which in turn causes this neuron to become stimulated. Through this process, signals are relayed throughout the central nervous system.
Habits that connect us � feather plucking and hair pulling
Mental health conditions are not unique to humans but can be seen throughout the animal kingdom. For example, trichotillomania is seen widely in many species, from mice to sheep, and in dogs and cats. Even in birds, a similar condition is seen, called pterotillomania, in which a bird will pluck out its own feathers. This condition is very common in captive birds, affecting around 10% of captive parrots and up to 65% of egg-laying hens.
One possible explanation for why all these species develop similar behavioural conditions is that the fundamental processes of the brain evolved together in a single common ancestor. These processes are essential for brain functioning and so they are highly conserved in all these species. This can be seen by comparing the structure of the brain’s serotonin receptor, 5-HT1A, an essential component of a functioning brain, in humans and birds.
There are 7 classes of serotonin receptors in humans, but 5-HT1A is the most widespread in the brain. Below you can see how similar the human and chicken 5-HT1A structures really are. In fact, they have a sequence similarity of over 85%. They are in the GPCR-family of proteins, which are found in the plasma membrane of neurons. This family has a distinct structure of 7 transmembrane alpha helices, 3 extracellular loops and an amphipathic helix on the intracellular side of the protein. We can easily compare these structures because of the recent advances in protein structure prediction. The chicken 5-HT1A was one of over 200 million high-quality predictions of protein structures released on AlphaFold DB in 2022.
Although the neurological basis for trichotillomania and pterotillomania is still poorly understood, serotonin receptors have been associated with conditions associated with impulse control and repetitive behaviours. It has been shown that young birds with higher tendencies to pluck feathers have lower turnover of serotonin. In humans, Serotonin-increasing drugs (SSRIs) can show a limited improvement in the symptoms of trichotillomania. Unfortunately, these drugs can have severe side effects and so behavioural therapy remains the recommended treatment for the condition. Therefore, we still have a lot to learn about these conditions and their relationship with neurotransmitters.
7E2Y - A landmark structure of the human Serotonin Receptor
In a 2021 paper in the Journal Nature, Xu et al. presented the very first cryo-EM protein structures of the serotonin receptor 5-HT1A. They were able to solve structures of 5-HT1A in the unbound state, with serotonin bound and with the antipsychotic drug, Aripirazole bound. These structures show precisely how 5-HT1A is activated by serotonin and the binding mode of drugs that mimic serotonin binding. Interestingly, the receptor can be activated in the absence of serotonin or drugs. The cause of this basal activity was shown to be due to the coordination of water into the serotonin binding site, which mimics the serotonin-bound state. By understanding how drugs bind to serotonin receptors, we may be able to develop the next generation of drugs that can be used to treat neurological conditions.
Did you know?
Serotonin is a molecule that was first produced by organisms very early during evolution. As a result, it is utilised for a wide variety of processes throughout all the kingdoms of life:
- Serotonin is one of the mild poisons used by stinging nettles. When brushed against, the stinging nettle injects a mix of irritants, including serotonin, into its target.
- Over 90% of all serotonin in humans is produced in the gut to promote healthy digestion. Serotonin is released in parts of the gut that contain food, which causes the contractions that move food through the intestines.
- An elevation of serotonin in locusts makes them more sociable and causes them to gather into vast swarms.
Marcus Bage
About the artwork
Charlotte, Drawing
Year 10 from Leventhorpe School (Hertfordshire, UK)
Laughter accelerates circulation and helps muscles relax, which can reduce the physical symptoms of stress. Laughing activates the release of serotonin, which affects your entire body. It is understood that Serotonin impacts animal cognition and behaviour. Deficiency in serotonin can predispose birds to develop feather pecking. This inspired me to create an artwork based on serotonin and my favourite bird, the toucan.
View the artwork in the virtual 2022
Structures mentioned in this article
(Explore the featured structure in 3D at )
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