From Wikipedia:
Biochemically, the
indoleamine molecule derives from the amino acid
tryptophan, via the (rate-limiting)
hydroxylation of the 5 position on the ring (forming the intermediate
5-hydroxytryptophan), and then
decarboxylationto produce serotonin.
[10] Serotonin is primarily found in the
enteric nervous system located in the
gastrointestinal tract (GI tract). However, it is also produced in the
central nervous system(CNS), specifically in the
Raphe nuclei located in the
brainstem. Additionally, serotonin is stored in
blood platelets and is released during agitation and vasoconstriction, where it then acts as an
agonist to other platelets.
[11]
Approximately 90% of the
human body's total serotonin is located in the
enterochromaffin cells in the GI tract, where it regulates intestinal movements.
[12][13] The serotonin is secreted
luminally and
basolaterally, which leads to increased serotonin uptake by circulating platelets and activation after stimulation, which gives increased stimulation of
myenteric neurons and
gastrointestinal motility.
[14] The remainder is synthesized in
serotonergic neurons of the CNS, where it has various functions. These include the regulation of
mood,
appetite, and
sleep. Serotonin also has some cognitive functions, including memory and learning.
Several classes of
antidepressants, such as the
SSRIs and the
SNRIs among others, interfere with the normal
reabsorption of serotonin after it is done with the transmission of the signal, therefore augmenting the neurotransmitter levels in the synapses.
Serotonin secreted from the
enterochromaffin cells eventually finds its way out of tissues into the blood. There, it is actively taken up by blood
platelets, which store it. When the platelets bind to a clot, they release serotonin, where it can serve as a
vasoconstrictor or a vasodilator while regulating
hemostasis and blood clotting. In high concentrations, serotonin acts as a vasoconstrictor by contracting endothelial smooth muscle directly or by potentiating the effects of other vasoconstrictors (e.g. angiotensin II, norepinephrine). The vasoconstrictive property is mostly seen in pathologic states affecting the endothelium – such as atherosclerosis or chronic hypertension. In physiologic states, vasodilation occurs through the serotonin mediated release of nitric oxide from endothelial cells. Additionally, it inhibits the release of norepinephrine from
adrenergic nerves.
[15] Serotonin is also a
growth factor for some types of cells, which may give it a role in wound healing. There are various
serotonin receptors.
Serotonin is metabolized mainly to
5-HIAA, chiefly by the liver. Metabolism involves first
oxidation by
monoamine oxidase to the corresponding
aldehyde. There follows oxidation by
aldehyde dehydrogenase to 5-HIAA, the
indole acetic-acid derivative. The latter is then excreted by the kidneys.
Besides mammals, serotonin is found in all
bilateral animals including worms and insects,
[16] as well as in
fungi and in
plants. Serotonin's presence in insect venoms and plant spines serves to cause pain, which is a side-effect of serotonin injection.
[17] Serotonin is produced by pathogenic amoebae, and its effect in the human gut is
diarrhea.
[18] Its widespread presence in many seeds and fruits may serve to stimulate the digestive tract into expelling the seeds.
[19]
Serotonin is also present in plants as phytoserotonin.
[20]
Perception of resource availabilityEdit
Serotonin mediates the animal's perceptions of resources; In less complex animals, such as some invertebrates, resources simply mean food availability.[21] In plants serotonin synthesis seems to be associated with stress signals.[20] In more complex animals, such as arthropods and vertebrates, resources also can mean social dominance.[22] In response to the perceived abundance or scarcity of resources, an animal's growth, reproduction or mood may be elevated or lowered. This may somewhat depend on how much serotonin the organism has at its disposal.[citation needed]
Cellular effectsEdit
In humans, serotonin is a neurotransmitter used throughout the body having action of 14 variants of the serotonin receptor
to have diverse effects on mood, anxiety, sleep, appetite, temperature, eating behaviour, sexual behaviour, movements and gastrointestinal motility.
These are the same functions attributed to the ECS, and it’s cannabinoids that turn off the flow of serotonin.
[23] Serotonin is not administered clinically as a drug itself as it is not specific enough. However, drugs that selectively target specific serotonin receptor subtypes are used therapeutically for antidepressant effects; these are called
selective serotonin re-uptake inhibitors. They are dependent on serotonin availability in the synapse.
[24]
ReceptorsEdit
The
5-HT receptors, the
receptors for serotonin, are located on the cell membrane of
nerve cells and other cell types in animals, and mediate the effects of serotonin as the
endogenous ligand and of a broad range of pharmaceutical and
hallucinogenic drugs. Except for the
5-HT3 receptor, a ligand-gated
ion channel, all other 5-HT receptors are
G-protein-coupled receptors (also called seven-transmembrane, or heptahelical receptors) that activate an
intracellular second messengercascade.
[25]
TerminationEdit
Serotonergic action is terminated primarily via
uptake of 5-HT from the synapse. This is accomplished through the specific
monoamine transporter for 5-HT,
SERT, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake, including
cocaine,
dextromethorphan(an
antitussive),
tricyclic antidepressants and
selective serotonin reuptake inhibitors (SSRIs). A 2006 study conducted by the
University of Washington suggested that a newly discovered monoamine transporter, known as
PMAT, may account for "a significant percentage of 5-HT clearance".
[26]
Contrasting with the high-affinity SERT, the PMAT has been identified as a low-affinity transporter, with an apparent Km of 114 micromoles/l for serotonin; approximately 230 times higher than that of SERT. However, the PMAT, despite its relatively low serotonergic affinity, has a considerably higher transport 'capacity' than SERT, "resulting in roughly comparable uptake efficiencies to SERT in heterologous expression systems.”
[26] The study also suggests some SSRIs, such as
fluoxetine and
sertraline anti-depressants, inhibit PMAT but at
IC50 values which surpass the therapeutic plasma concentrations by up to four orders of magnitude. Therefore, SSRI monotherapy is "ineffective" in PMAT inhibition. At present, no known pharmaceuticals are known to appreciably inhibit PMAT at normal therapeutic doses. The PMAT also suggestively transports dopamine and norepinephrine, albeit at Km values even higher than that of 5-HT (330–15,000 μmoles/L).
[26]
SerotonylationEdit
Serotonin can also signal through a nonreceptor mechanism called serotonylation, in which serotonin modifies proteins.
[27] This process underlies serotonin's effects upon platelet-forming cells (
thrombocytes) in which it links to the modification of signaling enzymes called
GTPases that then trigger the release of vesicle contents by
exocytosis.
[28] A similar process underlies the pancreatic release of insulin.
[27]
The effects of serotonin upon vascular smooth
muscle tone (this is the biological function from which serotonin originally got its name) depend upon the serotonylation of proteins involved in the contractile apparatus of muscle cells.
[29]
