Bringing Structure to Biology
Today’s good mood is sponsored by serotonin
Our well-being is a result of various types of factors combined together: biological (hormones and chemicals), psychological (personality), and environmental (everyday stress). Hormones control everything from the way our body functions to how we feel. One such hormone is serotonin. Any impairment in serotonin homeostasis can result in neurological and psychological disorders such as depression, anxiety, or aggression.
Two faces of serotonin
Serotonin (5-hydroxytryptamine or 5-HT) is a small molecule that functions both as a neurotransmitter in the central and enteric nervous system and as a hormone travelling through the bloodstream to different organs and tissues. While the role of serotonin in the brain is linked with mood regulation and brain function, it also has important jobs in other parts of our body. In the gut it contributes to normal bowel function, nutrient absorption, gastrointestinal innate immune system, and the microbiome. Serotonin secreted into the blood is bound to platelets in order either to be stored or to regulate vasoconstriction and blood clotting.
Most commonly, people are aware of serotonin’s role in the brain, but in fact, up to 90% of our body’s serotonin is produced in the gut. Here, the synthesis and secretion of serotonin occurs via specialized enteroendocrine cells (called enterochromaffin cells) in response to food presence in the lumen. If irritants are present in the food, the enterochromaffin cells release more serotonin to make the gut move faster in order to empty the gut of noxious food. The enterochromaffin cells not only react to bad food, but they are also very sensitive to radiation and cancer chemotherapy, which can trigger feelings of nausea and vomiting.
The synthesis of serotonin. L-tryptophan is hydroxylated at position 5 of the ring to form 5-hydroxy-L-tryptophan by the enzyme tryptophan hydroxylase. 5-hydroxy-L-tryptophan is then decarboxylated by 5-hydroxytryptophan decarboxylase to form serotonin.
Serotonin receptors – structural differences
Serotonin exerts its diverse actions by binding to distinct serotonin receptors that are located on the cell membrane. Among the seven different serotonin receptor classes (5-HT1 through 5-HT7) identified so far in humans, five (5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT7) are expressed in the gut. Interestingly, 5-HT3 receptors are ligand-gated ion channels and are, therefore, structurally and functionally distinct from the other six classes of serotonin receptors which are all coupled to G-proteins (GPCR).
The overall structure of GPCRs consists of an extracellular N-terminus, followed by seven transmembrane α-helices connected by three intracellular and three extracellular loops, an amphipathic helix 8, and intracellular C-terminus. The tertiary structure of this type of serotonin receptors resembles a barrel with the ligand binding site within.
In contrast, 5-HT3 receptors are either homopentameric, composed of five identical subunits (5-HT3A) or heteropentameric consisting of a mixture of 5-HT3A and one member from any of the other four serotonin subunits (5-HT3B-E). 5-HT3 receptors have three distinct domains – a twisted β-sandwich N-terminal extracellular domain, a transmembrane domain formed by four α-helices, and a large intracellular domain between transmembrane helices 3 and 4. The extracellular domain is the site of action of agonists and competitive antagonists while the transmembrane domain contains the central ion pore. N-terminal glycosylation is critical for subunit assembly, plasma membrane targeting, ligand binding, and calcium influx.
Structural organization of serotonin receptors. Crystal structure of a) pentameric serotonin receptor 5-HT3 (PDB 6HIQ), b) one subunit of serotonin receptor 5-HT3. c) General topology of serotonin receptor 5-HT3. Cryo-EM structure of d) serotonin receptor 5-HT1B (rainbow) coupled to heterotrimeric G-protein (PDB 6G79), e) serotonin receptor 5-HT1B. f) General topology of serotonin receptor 5-HT1B. Structures of serotonin receptors 5-HT3 and 5-HT1B were generated using PyMOL. Images d) and f) Sarkar, P., Mozumder, S., Bej, A. et al. Structure, dynamics and lipid interactions of serotonin receptors: excitements and challenges. Biophys Rev 13, 101-122 (2021).
Agonists and antagonists
The signalling mechanism and efficiency of serotonin receptors depend on their ability to rapidly access multiple conformational states. This conformational plasticity, necessary for the wide variety of functions displayed by serotonin receptors, is regulated by binding to various ligands.
Serotonin receptors act as drug targets for a number of human diseases, including depression, schizophrenia, anxiety, panic disorders, migraine, hypertension, eating disorders, and irritable bowel syndrome. These drugs can either act as agonists (stimulators) of specific serotonin subtypes or as antagonists (blockers) of specific serotonin subtypes.
People suffering from mood disorders often have imbalances in certain neurotransmitters, particularly serotonin, dopamine, norepinephrine, and endorphin. Serotonin level imbalance may influence the mood in a way that leads to depression. The major therapeutic agents for treating depression are antidepressants. These are mostly selective serotonin reuptake inhibitors (e.g. Prozac) or combined serotonin/noradrenaline reuptake inhibitors (e.g. Effexor). The mechanism of these medications is believed to prevent serotonin from being reabsorbed by the body, thus the serotonin levels stay high. Serotonin then stays in the synaptic gap longer than it normally would and may repeatedly stimulate the receptors of the recipient cell.
Unfortunately, as with many other drug molecules, serotonin receptor-targeting drugs often interact with more than a single target and the unintended interactions can lead to side effects. The development of drugs that selectively target serotonin receptors has proved to be extremely difficult, but it opens new possibilities for more effective and safer pharmacotherapy.
Serotonin receptors in PDB
By early 2013, the first structures of serotonin receptors 1B and 2B (PDB 4IAR, 4IAQ) were solved by X-ray crystallography. The improvements of methods for the analysis of membrane proteins helped to determine high-resolution structures of serotonin receptors. From 2013 to 2021, 48 structures from 11 serotonin receptor subtypes were experimentally determined. The largest group of serotonin receptors in the PDB is the 5HT3 type, with 16 of them available to date. The structures of serotonin receptors are present in the database with a variety of ligands, including serotonin (PDB 6HIQ), ergotamine (PDB 4IAR), LSD (PDB 6WGT), and palonosetron (PDB 6Y1Z).
Did you know?
- About one in a million neurons in the central nervous system synthesize serotonin.
- Psychedelic drugs like LSD, mescaline, and psilocybin act via serotonin receptors in the brain and can cause perception-altering effects such as visual and auditory hallucinations.
- The gut microbiota has the ability to affect not only the gut, but also the mind. The gut microbiota can interact with the chemical messengers (e.g. serotonin) involved in the transmission of information between gut and the brain, thus the gut microbiota can influence neural development, brain chemistry and wide range of behavioural phenomena. Human gut is often referred to as the ‘second brain’. So, don’t underestimate your gut feelings!
About the artwork
Charlotte Agnew acrylic on canvas
I have researched the Serotonin receptor as it relates to mental health, which is currently a huge factor in our society. I have used the idea that a lack of serotonin causes depressive moods, which I have conveyed by the warmer and cooler colours representing happiness and sadness. The coil like forms in the background connecting the figures are close ups of the receptors from the PDB that I manipulated.
(Explore in 3D at PDBe.org/6hiq/3d)
View the artwork in the virtual 2020 PDB Art exhibition.