Structure
The 5-HT3 receptor is bullet-shaped and consists of five subunits (A-E) that form an oligomer. In the center of this pentamer of subunits is a ligand-gated ion channel full of water, which the five subunits enclose pseudo-symmetrically. Each subunit of the 5-HT3 receptor consists of three regions; the extracellular region, the transmembrane region, and the intracellular region[1].
The extracellular region is relatively large compared to the other two regions, and contains a short C-terminus and a larger N-terminus. The N-terminus of the extracellular region is where the ligand binding occurs, and therefore deals with the agonists and antagonists[2].
These binding sites are located between two bordering subunits, assembled from three alpha-helices of one subunit and three beta-strands from the other subunit. Such connection creates a binding pocket with a small, select number of residues from each subunit pointed into the binding pocket, as opposed to the large remainder of residues that are pointing away from the binding pocket[3]. This binding pocket shrinks around agonists, encapsulating them, and widens around antagonists, repulsing them.
The transmembrane region is within the C-terminus region, and contains four alpha-helical domains within it (M1-M4) that stretch the length of this inner, transmembrane area. These four alpha-helical domains conduct the channel openings via ion selectivity, depending on both charge and size[3]. M2, the porous domain, contains rings of charged amino acids at both its start and its end, accounting for M2’s main contribution to ion selectivity. The M3 and M4 alpha-helices create a large loop with one another, thus assembling the intracellular region [1].
Function
This receptor plays a role in multiple processes throughout the brain and gastrointestinal tract. First, this receptor is responsible for altering anxiety levels. Research has indicated that several 5-HT3 antagonists are responsible for lowering anxiety. These antagonists prevent serotonin from binding to the receptor and increase the level of serotonin in the synapse, ultimately lowering anxiety levels[4]. Second, these receptors play a role in emesis. These receptors can be found at the end of the vagus nerve located in the digestive tract, and when serotonin binds there is a stimulation of the vomiting reflex causing individuals to become ill[5]. Finally, 5-HT3 receptors are bound to mucosal endings in the stomach and upon their activation can trigger motor neurons found in the intestine[6]. Depending on what the function of the motor neurons are, processes like secretion and peristalsis can be altered.
As previously mentioned this receptor has both extracellular and transmembrane domains, each serving a different function. The extracellular domain operates through ligand binding in which competitive inhibitors can bind and interfere with carrying out the functions mentioned. The transmembrane domain serves to help with ion selectivity and electrical conductance and if altered can also affect signaling of any of the processes mentioned[7].
Medical Implications
The 5-HT3 receptor has been used to combat numerous disorders and illnesses. This receptor has had the most success treating the negative symptoms of irritable bowel syndrome (IBS), psychosis, mood-related disorders, and chemotherapy-induced vomiting [7].
While 5-HT3 is a serotonin receptor, it also has the unique ability to regulate the release of other neurotransmitters, like dopamine. This is useful in the treatment of psychotic disorders such as schizophrenia, which is directly related to high levels of dopamine. Some anti-psychotic medications like Ondansetron and Clozapine are 5-HT3 antagonists; meaning it inhibits the receptor’s ability to function and in turn reduces the amount of serotonin and dopamine utilized by the body [7]. By normalizing the concentration of dopamine in the body, the psychotic symptoms of schizophrenia diminish.
Anxiety, depression, and aggression have been linked to the 5-HT3 receptor. A study conducted by Morrison, Ricci, and Melloni (2015)[8] demonstrated that when anabolic androgenic steroid (AAS) – a steroid that has similar effects as testosterone; increases aggressive behavior and decreases anxiousness– was injected into hamsters, the amount of 5-HT3 receptors in areas of the brain known to be associated with anxiety and aggression decreased. They also found that AAS-induced anxiety could be negatated with the activation of 5-HT3 receptors[8]. However, other studies have shown that by deleting the 5-HT3 receptor gene in mice, anxious behavior increased[7]. It is possible that the 5-HT3 receptor plays a role in both instigating and inhibiting anxiolytic behaviors, but more research needs to be done to be conclusive. The 5-HT3 receptor has also been linked to depression. In a study conducted on mice with diabetes-induced depression, it was found that by administering a 5-HT3 antagonist, serotonin levels were able to normalize and depressive symptoms decreased[4].
Another way the 5-HT3 receptor has been used in medicine is by aiding in the treatment of substance abuse. When human subjects with an alcohol or morphine addictions were administered a 5-HT3 antagonist, their levels of drug consumption decreased drastically[7]. However, this decrease was not shown in subjects addicted to psychostimulants like cocaine. Most research done on treatment for addiction is on the level of cognitive behavioral changes implemented by a psychologist. By adding an 5-HT3 antagonist to the treatment plan in addition to cognitive behavioral therapy, the rate of relapse in patients can be predicted to decrease tremendously.
One of the most successful treatments involving 5-HT3 receptors is the treatment of chemotherapy-induced vomiting. The 5-HT3 receptor plays a key role in gag reflex because of the high concentration of this particular receptor in the dorsal vagal complex of the digestive tract, an area responsible for vomit initiation[9]. Studies have found that when there is a mutation in the promoter region of the 5-HT3B receptor gene, vomiting was reduced[7]. Patients receiving chemotherapy are already subjecting their bodies to an immense amount of stress, so by being able to relieve them of some adverse side-effects, might contribute to an overall better outcome for the patient.
The most well studied use of the 5-HT3 receptor is in combating IBS. The 5-HT3 receptor is found in high concentration on the mucosal membrane of the stomach, when this receptor is over activated, it can cause pain in the colon as well as an increased rate in the production of waste. When an antagonist of the receptor was administered to patients with IBS, their symptoms were alleviated<ref name="thompson">. This demonstrates the wide variety of possible medical treatments that include the utilization of 5-HT3 receptors and how much more there still is to be discovered.
- ↑ 1.0 1.1 Barnes, N., Hales, T., Lummis, S., & Peters, J. (2009). The 5-HT3 receptor – the relationship between structure and function. Neuropharmacology, 273-284
- ↑ Perumal, R., & Mahesh, R. (2006). Synthesis and biological evaluation of a novel structural type of serotonin 5-HT3 receptor antagonists. Bioorganic & Medicinal Chemistry Letters, 2769-2772.
- ↑ 3.0 3.1 Hassaine, G., Deluz, C., Grasso, L., Wyss, R., Tol, M., Hovius, R., . . . Nury, H. (2014). X-ray structure of the mouse serotonin 5-HT3 receptor. Nature, 276-281.
- ↑ 4.0 4.1 Gupta, D., Thangaraj, D., & Radhakrishnan, M. (2016). A novel 5HT3 antagonist 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide) prevents diabetes-induced depressive phenotypes in mice: Modulation of serotonergic system. Behavioural Brain Research, 297, 41-50. doi:10.1016/j.bbr.2015.10.007
- ↑ Serotonin - Receptors and effects. (n.d.). Retrieved November 14, 2015, from https://www.pharmacorama.com/en/Sections/Serotonin_2_2.php
- ↑ Galligan, J. J. (2002). Ligand-gated ion channels in the enteric nervous system. Neurogastroenterology & Motility, 14(6), 611-623. doi: 10.1046/j.1365-2982.2002.00363.x
- ↑ 7.0 7.1 7.2 7.3 7.4 7.5 Thompson, A. J., & Lummis, S. C. R. (2006). 5-HT3 receptors. Current Pharmaceutical Design, 12(28), 3615–3630.
- ↑ 8.0 8.1 Morrison, T. R., Ricci, L. A., & Melloni, R. H., Jr. (2015). Aggression and anxiety in adolescent AAS-treated hamsters: A role for 5HT3 receptors. Pharmacology Biochemistry and Behavior, 134, 85-91. doi:10.1016/j.pbb.2015.05.001
- ↑ Hannon, J., & Hoyer, D. (2008). Research report: molecular biology of 5-HT receptors. Behavioural Brain Research, 195(Serotonin and cognition: mechanisms and applications), 198-213. doi:10.1016/j.bbr.2008.03.020
