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Biochemistry, Serotonin

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Last Update: October 5, 2022.

Introduction

Serotonin is a monoamine neurotransmitter that plays a role in several complex biological functions.[1][2] Its common abbreviation is 5-HT because of its chemical name: 5-hydroxytryptamine. The attribution for the discovery of serotonin is that it occurred serendipitously by Vittorio Erspmarer during his attempt to purify extract from enterochromaffin cells in 1935.[3] 

Serotonin forms from the hydroxylation (i.e., the addition of -OH group) and decarboxylation of the tryptophan amino acid. The highest concentration of serotonin is in the enterochromaffin cells of the gastrointestinal tract, with small amounts in the central nervous system and platelets. Serotonin induces changes in the cell by its action on the serotonergic receptors, which are coupled to different G proteins mediating intracellular changes.[2]

The biological function of serotonin plays several roles in the human body, such as influencing learning, memory, happiness, and reward, as well as physiological processes such as regulation of sleep, behavior, and appetite.[4] Serotonin plays a significant role in the pharmacodynamic activities of antidepressants, such as SSRIs and SNRIS. This compound is not only found in mammals but is also present in insects, plants, and fungi. Therefore, the consumption of these organisms can affect serotonin levels in humans, occasionally leading to adverse effects.[1]

Fundamentals

Serotonin is a compound that functions in both the central nervous system and the peripheral nervous system. It acts in the form of the hormone, neurotransmitter, and mitogen in our body.[2] The compound was first discovered in the year 1935 by a Roman scientist name Vittorio Erspamer. The isolation of serotonin came as a result of researchers looking for a substance that platelets released, leading to vasoconstriction. It was also initially called enteramine following discovery due to its function of smooth muscle contraction in the gastrointestinal tract after its release from the enterochromaffin cells.[4]

Later, researchers identified that serotonin is also released as a neurotransmitter in the human brain. These excretory clusters of neurons became known as the serotonergic system. The various functions of serotonin in the CNS are comprehensive and relate to the action of the serotonergic system on the forebrain, brainstem, and cerebellum.[2] Projections from the rostral nuclei of this system help regulate temperature, appetite, sleep cycles, emesis, and sexual behavior. The most clinically relevant function of serotonin is in psychiatric disorders; most commonly, its absence appears to be related to depression, anxiety, and mania.[5][4]

 At the most simple level, serotonin functions by meditating an animal's perception of its own bodily resources. When the levels of basic resources such as food, water, and sleep are sufficient, the animal shows higher levels of serotonin, correlating to an increased perception of happiness.[5] However, when these physiological needs are lacking, an adverse effect occurs.[2] 

Cellular

There are seven subtypes of serotonin receptors present in the body.[2] Most subtypes exhibit heterogeneity and further subdivide into 5-HT1A, 5-HT2B, 5-HT3, etc. Six of these subtypes involve G-protein-coupled receptors.

The 5-HT receptor is unique in that it involves a ligand-gated Na/K ion channel similar to gamma-aminobutyric acid (GABA) and N-methyl-d-aspartic acid.[5] 

5-HT1 and 5-HT5 receptors negatively couple with adenylyl cyclase; the activation of these receptors downregulates cyclic AMP. 5-HT receptor upregulates the inositol triphosphate and diacylglycerol pathways, resulting in intracellular Ca release. A combination of 5-HT4, 5-HT6, and 5-HT7 receptors activate adenylyl cyclase, increasing cAMP activity.[4] 

The Na/K cation channel associates with 5-HT results in plasma membrane depolarization. The termination of serotonergic activity is facilitated by the reuptake of 5-HT from the cellular synapse. 

Molecular

Serotonin is a biogenic monoamine; its production occurs in two steps. The essential amino acid tryptophan is hydroxylated to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase. In a second step, 5-HTP undergoes decarboxylation to form 5-HT. Early studies have shown that hydroxylation and decarboxylation occur almost instantaneously in the presence of tryptophan.[2][4]

Serotonin is synthesized and stored within the central nervous system (CNS) in the presynaptic neurons (serotonergic neurons, pineal gland, and catecholaminergic neurons). Serotonin is present in nine groups of cell bodies isolated to the pons and midbrain. The raphe nuclei are the major nuclei, possessing both ascending serotonergic fibers that project to the forebrain as well as descending fibers extending to the medulla and spinal cord. A small number of serotonergic nuclei also reside in reticular formation with fibers that remain within the medulla.[6]

In the CNS, serotonin processing occurs in several ways. Upon neuronal depolarization, there is a release of serotonin into the synaptic cleft. It can bind to either postsynaptic serotonin receptors (5-HT receptors) or presynaptic serotonin autoreceptors.[1] 

Serotonin binding to the autoreceptor acts as negative feedback against the further release of serotonin into the synaptic cleft. The highly selective serotonin transporter (SERT), which is located on the presynaptic membrane, functions to remove serotonin from the synaptic cleft.[7] Once transported into the presynaptic neuron, serotonin is recycled back into presynaptic vesicles, where it is protected from metabolism. Metabolism by monoamine oxidase (MAO) occurs within the cytosol of the neuron. An alternate pathway for serotonin exists in the pineal gland; it converts to melatonin.[2]

Serotonin originating from enterochromaffin cells is released into the portal circulation and undergoes rapid elimination from the plasma by way of uptake into platelets and liver metabolism. Serotonin transporters on the platelet membrane, and enterochromaffin cells function to uptake serotonin into those cells. Serotonin escapes uptake, and liver metabolism reaches the lung, where it then undergoes metabolism.[7] 

Function

Serotonin is a direct-acting neurotransmitter that is commonly stored in presynaptic vesicles. Upon activation of the nerve by adjacent nerve impulses, serotonin is released into the synaptic cleft, where it can bind to postsynaptic receptors.[1] These postsynaptic serotonin receptors, also known as 5-hydroxytryptamine receptors, either act as G-couple protein receptors or ligand-gated ion channels. This activation ultimately allows activation of a second intracellular messenger cascade producing either an excitatory or inhibitory response.[2] 

An estimated 90% of the serotonin in the human body is stored in enterochromaffin cells located in the gastrointestinal tract. Upon luminal and basolateral secretion, the compound is absorbed by circulating platelets. Once activated, serotonin functions to mobilize intestinal contraction and direction via the stimulation of myenteric neurons.[2][4] Although only 10% of serotonin is produced by neurons located in the central nervous system, it is for its function in the brain for which it is better known. The various functions of serotonin in the central nervous system include sleep, hunger, mood, memory, and learning management.

When excessive serotonin is released from the enterochromaffin cell, it frequently is introduced to the bloodstream, where it interacts with blood platelets. The platelets absorb the serotonin and store it until clot forms. However, once a clot forms, the serotonin is re-released in the blood, where it can regulate hemostasis and blood clotting.[8] At elevated levels, serotonin functions by contracting vascular smooth muscle cells leading to vasoconstriction. However, at lower levels, serotonin facilitates endothelial class to release nitric oxide leading to vasodilation.[8]

Testing

The liver metabolizes excess serotonin into a compound known as 5-HIAA. This process of metabolism begins with the oxidation of the compound to an aldehyde by a monoamine oxidase. The aldehyde is then further oxidation by aldehyde dehydrogenase into 5-HIAA.[6] The end product is then excreted through the urine. When the body is producing excess levels of serotonin, one may expect to see increased levels of 5-HIAA in the urine or blood. 

Clinical Significance

Serotonin plays a critical role in the human body. Over the last 70 years, researchers have been able to obtain a great understanding of which disease processes are influenced by this neurotransmitter, as well as its therapeutic properties in potential medical interventions.

It appears to play an essential role in the central nervous system (CNS) and the body's general functioning and, in particular, the gastrointestinal (GI) tract. Studies have shown links between serotonin and bone metabolism, the production of breast milk, liver regeneration, and cell division.

Serotonin influences the brain cells both directly and indirectly.

Bowel Function

Most of the body's serotonin is in the GI tract, where it regulates bowel function and movements. The human digestive tract is composed of several layers of enterochromaffin cells. These cells sense food in the stomach and release serotonin as a response. Increased serotonin levels in the gut cause digestive processes to increase in speed, which often occurs as a result of digesting toxins or noxious substances. It also plays a part in reducing appetite while eating.[2]

Mood

Serotonin plays a significant role in the nervous system and, therefore, largely affects mood. In the brain, serotonin changes mood, anxiety, and happiness by increasing nerve stimulation and electrical impulses. Drugs like ecstasy and LSD increase the levels of serotonin in the brain to produce effects like increased appetite, increased sexual drive, euphoria, and even hallucinations.[7]

Clotting

When serotonin is released into the blood, it is often absorbed by platelets rather than remaining free serotonin. The effect serotonin has on the platelets is similar to those produced by the interaction of platelet factor 2 and platelets. Serotonin accelerates the metabolism of fibrinogen to fibrin. This action causes platelet aggregation leading to vasoconstriction, and the result is a reduction in the blood flow and an increase in clot formation; this is one of the earliest defined functions of serotonin.[8]

Nausea

When serotonin is released into the gut faster than it can be digested, it is oven reabsorbed into the bloodstream. In the bloodstream, the neurotransmitter can interact with 5-HT3 receptors, which in turn activate chemoreceptor trigger zones. The activation of these sites causes stimulation of the brain to cause expulsion of the substance eaten; this is perceived as nausea by us.[6]

Bone Density

Several research studies have shown that it may have links to a decrease in bone density, but the relationship lacks sufficient proof. This correlation has been hypothesized by an early study that measured the changes in mice that lacked brain serotonin. The researchers found that these mice have severe osteopenia, while mice that only lack intestinal serotonin have regular bone density. Humans with increased levels of blood serotonin have been linked to increased or regular bone density. The belief is that the 5-HT1B receptor is the link between blood serotonin and bone density.[9] 

Sexual Function

Serotonin has been linked to increased sexual drive but decreased sexual function; this can be rather detrimental to patients who have received a prescription for selective serotonin reuptake inhibitors (SSRIs). As these drugs are commonly given to patients suffering from depression, they can often exacerbate the underlying problem due to sexual tension. The main course of serotonin's role in decreased sexual function is increasing retrograde ejaculation and erectile dysfunction. The cause of these symptoms is due to overstimulation of the 5-HT2C receptors, which promote erection and inhibit ejaculation, and the under-stimulation of the 5-HT1A receptor, which has the inverse functions.[10]

Review Questions

References

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Coleman JA, Yang D, Zhao Z, Wen PC, Yoshioka C, Tajkhorshid E, Gouaux E. Serotonin transporter-ibogaine complexes illuminate mechanisms of inhibition and transport. Nature. 2019 May;569(7754):141-145. [PMC free article: PMC6750207] [PubMed: 31019304]
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Weaver SR, Xie C, Charles JF, Hernandez LL. In utero and lactational exposure to the Selective Serotonin Reuptake Inhibitor fluoxetine compromises pup bones at weaning. Sci Rep. 2019 Jan 18;9(1):238. [PMC free article: PMC6338725] [PubMed: 30659249]
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Ivetic N, Arnold DM, Smith JW, Huynh A, Kelton JG, Nazy I. A platelet viability assay (PVA) for the diagnosis of heparin-induced thrombocytopenia. Platelets. 2019;30(8):1017-1021. [PubMed: 30693813]
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Frost M, Andersen TE, Yadav V, Brixen K, Karsenty G, Kassem M. Patients with high-bone-mass phenotype owing to Lrp5-T253I mutation have low plasma levels of serotonin. J Bone Miner Res. 2010 Mar;25(3):673-5. [PubMed: 20200960]
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Zainol M, Sidi H, Kumar J, Das S, Ismail SB, Hatta MH, Baharuddin N, Ravindran A. Co-Morbid Erectile Dysfunction (ED) and Antidepressant Treatment in a Patient - A Management Challenge? Curr Drug Targets. 2019;20(2):182-191. [PubMed: 28302034]
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