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Hormone Assignment

on 8 October 2014

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Transcript of Melatonin

Structure of Melatonin
Known as
'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
to serotonin.2,3

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.

Melatonin Pathways
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
suprachiasmatic nucleus
(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

Physiological actions
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)

New Research
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.
(Figure 9)

Tryptophan 5-hydroxylase

L-amino acid decarboxylase

Arylalkylamine N-acetyltransferase (AANAT)

N-Acetyl Serotonin


Figure 3: The body's circadian rhythm is maintained with the assistance of melatonin.

More Synthesis


SCN and neural retina
MLT2 receptors: brain and periphery
Taken exogenously,as a
prescription pill or
dietary supplement,
melatonin tablets induce
a natural sleep for
those suffering from
jet lag


Melatonin tablets
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.
(Figure 6)
Although coupled to different G proteins, both membrane receptor subtypes negatively bind to adenylyl cyclase mediating an
inhibitory effect.

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)
Melatonin receptors

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
Figure 4
(http//www.picscience.net/images an3.jpg)
(http//www.picscience.net/images an3.jpg)
Tranduction pathways of Melatonin
Figure 12: Bottling the Fountain of Youth
Figure 6:
Figure 5: Distribution of melatonin membrane receptors
Figure 8:Melatonin opens the sleepgate
Figure 9:Melatonin makes me sleepy
Figure 7
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
1. Cipolla‐Neto J, Amaral FG, Afeche SC, Tan DX, Reiter RJ. Melatonin, energy metabolism and obesity: a review. J Pineal Res. 2014;56(4):371-81.

2. Macchi MM, Bruce JN. Human pineal physiology and functional significance of melatonin. Front Neuroendocrinol. 2004;25:177-95.

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.

4. Pandi-Perumal SR, Trakht I, Srinivasan V, Spence DW, Maestroni GJM, Zisapel N, Cardinali D. Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways. Prog Neurobiol. 2008;85,:335–53.

5. Claustrat B, Brun J, Chazo G. The basic physiology and pathophysiology of melatonin. Sleep Med Rev. 2005;9:11–24.

6. Matsuo M, Coon SL, Klein DC. RGS2 is a feedback inhibitor of melatonin production in the pineal gland. FEBS Lett. 2013;587:1392–98.

7. Tosini G, Iuvone MP, McMahon DG, Shaun P. The retina and circadian rhythms. New York (USA): Springer; 2013.

8. Bedrosian TA, Herring KL, Walton JC, Fonken LK, Weil ZM, Nelson RJ. Evidence for feedback control of pineal melatonin secretion. Neurosci Lett. 2013;542:123–5.

9. Figueiro MG, Wood B, Plitnick B, Rea MS. The impact of light from computer monitors on melatonin levels in college students. Neuro Endocrinol Lett, 2011;32(2):158-63.

10. Mazzoccoli G, Sothern RB, Francavilla M, De Petris MP, Giuliani F. Comparison of whole body circadian phase evaluated from melatonin and cortisol secretion profiles in healthy humans. Biomed Aging Pathol. 2011; 112–122.

11. Reiter RJ & Tan DX (2009). Pineal gland and melatonin. Encylocopedia of Neuroscience 713-717.

12. Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ. One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J. Pineal Res. 2007;42(1):28–42.

13. J. Barrenetxe, P. Delagrange, J. A. Martínez. Physiological and metabolic functions of melatonin. J Physiol Biochem. 2004;60(1):61-72.

14. Muhlbauer E, Albrecht E, Hofmann K, Bazwinsky-Wutschke I, Penschke E. Melatonin inhibits insulin secretion in rat insulinoma beta-cells (INS1) heterologously expressing the human melatonin receptor isofrom MT2. J Pineal Res. 2011;51(3):361-72.

15. Roy D, BelshamDD. Melatonin receptor activation regulates GnRH gene expression and secretion in GT1-7 GNRH neurons: signal transduction mechanisms. J Biol Chem. 2002;277:251–58.

More references
16. Carrillo-Vico A, Reiter RJ, Lardone PJ, Herrera JL, Fernández-Montesinos R, Guerrero JM et al. The modulatory role of melatonin on immune responsiveness. Curr Opin Investig Drugs. 2006;7(5):423–31.

17. Maestroni GJ. Therapeutic potential of melatonin in immunodeficiency states, viral diseases, and cancer. Adv Exp Med Biol. 1999;467:217–26.

18. Pieri C, Marra M, Moroni F, Recchioni R, Marcheselli F. Melatonin: a peroxyl radical scavenger more effective than vitamin E. Life Sci. 1994;55(15):271-76.

19. Zemkova H, Balik A, Stojilkovic. S. Expression and signal transduction pathways of melatonin receptors in pituitary. In: Pandi-Perumal SR, editor. Melatonin: biological basis of its function in health disease. Georgetown: Landes Bioscience; 2006 p. 88-105.

20. Anisimov V. Effects of exogenous melatonin-a review. Toxicol Pathol. 2003;31(6):589–603.

21. Sharman EH, Sharman KG, Ge YW, Lahiri DK, Bondy SC. Age-related changes in murine CNS mRNA gene expression are modulated by dietary melatonin. J. Pineal Res. 2004;36(3):165–70.

22. Rodella L, Favero G, Rossini C, Foglio E, Bonomini F, Reiter R, Rezzani, R. Aging and vascular dysfunction: beneficial melatonin effects. Age. 2013;35(1):103-15.

23. Bubenik, G., Konturek, S. Melatonin and aging prospects for human treatment. J Physiol Pharmacol. 2011;62(1):13-9.
Full transcript