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== 5-HT3a Receptor==
<StructureSection load='5-ht3a.pdb' size='650' side='right' caption='5-HT3a receptor' scene='71/716487/Default/1'>
5-Hydroxytryptamine receptors, commonly known as 5-HT receptors, bind with the neurotransmitter serotonin. There are seven families of 5-HT receptors (5-HT1- 5-HT7),  all of which function as G-protein-coupled receptors with the exception of the 5-HT3 group. This third group is part of the Cys-loop superfamily of ligand-gated ion channels<ref name="barnes" />. This article focuses specifically on the 5-HT3 receptors and how its structure contributes to its function. These functions include: altering anxiety level, influencing the vomiting reflex, increase of intestinal secretion and gastric motility. Although the exact structural model of the 5-HT3 receptor has not be definitively identified, through the process of homology modeling, using acetylcholine binding protein as a template, a structure has been inferred.
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== Structure ==

The <scene name='71/716487/Default/1'>5-HT3 </scene> 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<ref name="barnes">Barnes, N., Hales, T., Lummis, S., & Peters, J. (2009). The 5-HT3 receptor – the relationship between structure and function. Neuropharmacology, 273-284</ref>.


The <scene name='71/716487/Extracellular_region/1'>extracellular region</scene> 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<ref name="perumal">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.</ref>. 
These <scene name='71/716487/Binding_site/4'>binding sites</scene> 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 <scene name='71/716487/Default/11'> away</scene> from the binding pocket<ref name="hassaine">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.</ref>. This binding pocket shrinks around agonists, encapsulating them, and widens around antagonists, repulsing them. 

The <scene name='71/716487/Default/5'>transmembrane region</scene> 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<ref name="hassaine" />. M2, the porous domain, contains rings of charged amino acids at both its start and its <scene name='71/716487/Default/10'>end</scene>, accounting for M2’s main contribution to ion selectivity. The M3 and M4 alpha-helices create a large <scene name='71/716487/Default/6'> loop</scene> with one another, thus assembling the <scene name='71/716487/Default/7'>intracellular region</scene><ref name="barnes" />.  

== 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<ref name="gupta">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</ref>. 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<ref name="sero">Serotonin - Receptors and effects. (n.d.). Retrieved November 14, 2015, from http://www.pharmacorama.com/en/Sections/Serotonin_2_2.php</ref>.  Finally, 5-HT3 receptors are bound to mucosal endings in the stomach and upon their activation can trigger motor neurons found in the intestine<ref name="galligan">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</ref>. 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<ref name="thompson">Thompson, A. J., & Lummis, S. C. R. (2006). 5-HT3 receptors. Current Pharmaceutical Design, 12(28), 3615–3630.</ref>.

== 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 <ref name="thompson" />. 
	
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 <ref name="thompson" />. 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)<ref name="more">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</ref> demonstrated that when anabolic androgenic steroid (AAS) – a steroid that has similar effects as testosterone; increasing aggressive behavior and decreasing 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 negated with the activation of 5-HT3 receptors<ref name="more" />. However, other studies have shown that by deleting the 5-HT3 receptor gene in mice, anxious behavior increased<ref name="thompson" />. 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<ref name="gupta" />. 
	
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<ref name="thompson" />. However, this decrease was not shown in subjects addicted to psychostimulants like cocaine. Most of the research conducted on treatment for addiction is on the level of cognitive behavioral changes implemented by a psychologist. By combining 5-HT3 antagonist therapy and 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<ref name="hannon">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</ref>. Studies have found that when there is a mutation in the promoter region of the 5-HT3B receptor gene, vomiting was reduced<ref name="thompson" />. Patients receiving chemotherapy subject their bodies to immense amounts of stress; being able to relieve them of some adverse side-effects, might contribute to an overall better prognosis 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 waste production. 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. 



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== References ==
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