Biochemistry, Serotonin

Fundamentals

Serotonin is a compound that functions in both the central and peripheral nervous systems. It acts in the form of the hormone, neurotransmitter, and mitogen in our body.[2] The compound was first discovered in 1935 by a Roman scientist named Vittorio Erspamer. The isolation of serotonin resulted from researchers looking for a substance that platelets released, leading to vasoconstriction. It was also initially called enteramine following its 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 central nervous system 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 simplest level, serotonin meditates an animal's perception of its bodily resources. When the levels of basic resources such as food, water, and sleep are sufficient, the animal shows higher serotonin levels, correlating to an increased perception of happiness.[5] However, when these physiological needs are lacking, an adverse effect occurs.[2] 

Cellular Level

There are 7 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 because it involves a ligand-gated Na/K ion channel similar to gamma-aminobutyric acid 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, releasing intracellular Ca. A combination of 5-HT4, 5-HT6, and 5-HT7 receptors activate adenylyl cyclase, increasing cAMP activity.[4]  The Na/K cation channel is associated with 5-HT, which depolarizes the plasma membrane. The termination of serotonergic activity is facilitated by the reuptake of 5-HT from the cellular synapse. 

Molecular Level

Serotonin is a biogenic monoamine; its production occurs in 2 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 in the presynaptic neurons (serotonergic neurons, pineal gland, and catecholaminergic neurons). Serotonin is present in 9 groups of cell bodies isolated to the pons and midbrain. The raphe nuclei are the major nuclei, possessing ascending serotonergic fibers that project to the forebrain and descending fibers extending to the medulla and spinal cord. A few serotonergic nuclei also reside in reticular formation with fibers within the medulla.[6]

In the central nervous system, serotonin processing occurs in several ways. Upon neuronal depolarization, serotonin is released 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), located on the presynaptic membrane, removes serotonin from the synaptic cleft.[7] Once transported into the presynaptic neuron, serotonin is recycled back into presynaptic vesicles, 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, which then undergoes metabolism.[7] 

Function

Serotonin is a direct-acting neurotransmitter that is commonly stored in presynaptic vesicles. Upon nerve activation by adjacent nerve impulses, serotonin is released into the synaptic cleft, where it can bind to postsynaptic receptors.[1] These postsynaptic serotonin receptors, 5-hydroxytryptamine receptors, either act as G-couple protein receptors or ligand-gated ion channels. This activation ultimately allows the activation of a second intracellular messenger cascade, which produces 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 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 a 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 the endothelial class to release nitric oxide, leading to vasodilation.[8]

Testing

The liver metabolizes excess serotonin into a compound known as 5-HIAA. This metabolism process begins with the oxidation of the compound to an aldehyde by a monoamine oxidase. The aldehyde is then further oxidated by aldehyde dehydrogenase into 5-HIAA.[6] The end product is then excreted through the urine. When the body produces excess serotonin levels, 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 gained a thorough understanding of which disease processes are influenced by this neurotransmitter and its therapeutic properties in potential medical interventions. It appears to play an essential role in the central nervous system and the body's general functioning, particularly the gastrointestinal tract. Studies have shown links between serotonin and bone metabolism, breast milk production, 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 gastrointestinal tract, regulating 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 speed, often due to 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 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, resulting in a reduction in the blood flow and an increase in clot formation; this is 1 of the earliest defined functions of serotonin.[8]

Nausea

When serotonin is released into the gut faster than it can be digested, it is reabsorbed into the bloodstream in the oven. In the bloodstream, the neurotransmitter can interact with 5-HT3 receptors, activating 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 lacking intestinal serotonin have regular bone density. Humans with increased blood serotonin levels 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 cause of serotonin's role in decreased sexual function is increasing retrograde ejaculation and erectile dysfunction. The cause of these symptoms is the overstimulation of the 5-HT2C receptors, which promote erection and inhibit ejaculation, and the under-stimulation of the 5-HT1A receptor, which has inverse functions.[10]