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Transcript of Melatonin
'the hormone of darkness'
this ancient molecule is found everywhere in nature.1
Identified in 1958 as the indolamine N-Acetyl-5-methoxytryptamine hormone (Figure 1)
Named due to its ability to affect frog skin melanophores and its chemical relation
Synthesis occurs in various cells, tissues and organs including the retina, GI tract, skin, lymphocytes and bone marrow, in mammals4
Circulating melatonin is produced by the pineal gland and released in blood and cerebrospinal fluid (CSF).1
Synthesis is initiated by the uptake of the amino acid tryptophan from the blood.
Sequential enzymatic steps converts tyrptophan into melatonin in the pineal gland.5 (Table 1)
Melatonin is the hormone of darkness and secretion increases during the darkness of night
and falls to low levels during the light of day.
The fluctuations in the release of melatonin entrain the body’s biological rhythms to the external light-darkness cues thereby maintaining the circadian rhythm at 24 hours.(Figure 3)
One released, melatonin’s ampiphilic properties allow it to travel freely in the blood, easily diffuse across cell membranes into all tissues, and into all cellular compartments.10
The sleep hormone
There is no current evidence of feedback control of melatonin secretion.
However, melatonin can adjust its own receptor activity in the SCN in rats.
Studies show an increase in melatonin receptor density after several days of exposure to constant light but an injection of melatonin reversed this effect within 4 hours.
The study concluded that melatonin levels may increase during early evening, providing feedback to the pineal gland to stop melatonin production by the middle of the night as melatonin concentrations would been seen to decrease during the late evening.
Figure 1: The Chemical composition melatonin
Paraventricular nucleus of the hypothalamus
- site of melatonin production.
It activates sympathetic preganglionic neurons in the upper section of spinal cord which innervates sympathetic postganglionic neurons to the pineal gland.1
Controlled by the
(SCN) of the hypothalamus, known as the master circadian clock.1
The SCN is connected to light–dark cycles and synthesis is activated or deactivated by light perceived by the retinal ganglion cells (RGCs).4
RGC’s are connected to the SCN through the retinohypothalamic tract. 4
During the night, signals from the SCN trigger noradrenaline release through G-protein-coupled adrenergic receptors into the pineal perivascular space, increasing cAMP and hence melatonin synthesis. 6
One of melatonins' role in
is its ability to synchronize many biological rhythms in the body.
Although best known for its
chronobiotic role in the body’s circadian rhythm,
melatonin’s physiological actions are wide and varied depending on its site of action.
has been described as an
is linked to seasonal breeding, migration and hibernation in animals4 (Figure 9).
regulator of reproduction12,
the most powerful antioxidant17,
a controller of prolactin and gonadotropin release18,
a free radical scavenger17,
a modulator of insulin13 (Figure 10)
Melatonin: Bottling the Fountain of Youth
As we age, our melatonin levels drop, or is it that we age
our melatonin levels drop? New research strengthens the theory that melatonin plays a crucial part in the aging process.
When melatonin is administered to mice,levels of a protein named Sirtuin 1 (SIRT1) are increased. SIRT1 has been shown to increase life expectancy.21
Another research group interested in this link between aging and melatonin has made a connection between hunger and melatonin production. Hungry mice produce more melatonin in their gut and live 20% longer.
They conclude that skipping the hunger and just taking exogenous melatonin will have the same effect. This is also being trialled on humans.22
With melatonin’s strong antioxidant properties protecting the body from free radicals, its increased production in the gut during times of age extending starvation, and a link to increasing the levels of life extending protein SIRT1, melatonin could be the fountain of youth.
L-amino acid decarboxylase
Arylalkylamine N-acetyltransferase (AANAT)
Figure 3: The body's circadian rhythm is maintained with the assistance of melatonin.
SCN and neural retina
MLT2 receptors: brain and periphery
Taken exogenously,as a
prescription pill or
melatonin tablets induce
a natural sleep for
those suffering from
Table 1: Enzymatic steps in melatonin synthesis
Figure 10:The many actions of melatonin
Melatonin’s complexity is a result of not only its many receptor sites, but also of its
many second messengers.
Although coupled to different G proteins, both membrane receptor subtypes negatively bind to adenylyl cyclase mediating an
Upon activation, melatonin membrane receptors in the SCN interact with Gi/GO α proteins which inhibit cAMP transduction cascades, effectively decreasing levels of protein kinase A (PKA) activity and nuclear factor CREB (camp responsive element binding protein) phosphorylation.
SCN neural firing is thus decreased, and the arousal system is inhibited, allowing the sleep gates to be opened. This is demonstrated by decreased body temperature; induced drowsiness, relaxation of smooth muscle in the GI tract and regulation of leptin levels.(Figure 7)
This pleiotrophic hormone regulates a variety of physiological and neuroendocrine functions by binding to
4 types of sites:
The two main hydrophillic membrane receptors; melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2) are
seven transmembrane domain G-coupled receptors
and are found mainly in the SCN and retina of the CNS.(Fig 4,5,6)
Nuclear lipophilic receptors RZR (Retinoid Z Receptor)/ROR (Retinoid Orphan Receptor) located in the brain and periphery.(Fig 5 )
Calmodulin (Figure 5)
A little known MT3 receptor site
Tranduction pathways of Melatonin
Figure 12: Bottling the Fountain of Youth
Figure 5: Distribution of melatonin membrane receptors
Figure 8:Melatonin opens the sleepgate
Figure 9:Melatonin makes me sleepy
Figure 11: Exogenous melatonin
Figure 2: Melatonin synthesis pathway
Arylalkylamine N-acetyltransferase is a melatonin precursor enzyme - the rate limiting enzyme in melatonin production3
Light striking the eyes inhibits nerve pathways that stimulate secretion 7,8 and degrades pineal AANAT. 4 (Figure 2).
Exposure to blue light from electronics decreases melatonin production.9
Even more Synthesis
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3. Slominski RM, Reiter RJ, Schlabritz-Loutsevitch N, Rennolds OS, Slominski AT. Melatonin membrane receptors in peripheral tissues: distribution and functions. Mol Cell Endocrinol. 2012;351:152–66.
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