Melatonin is a hormone synthesized and secreted by the pineal gland in response to darkness. It regulates circadian rhythms by entraining the suprachiasmatic nucleus. Melatonin is derived from tryptophan and its synthesis involves the rate-limiting conversion of serotonin to N-acetylserotonin by the enzyme serotonin N-acetyltransferase. Light signals perceived by retinal ganglion cells are relayed to the suprachiasmatic nucleus which regulates melatonin secretion. Melatonin has antioxidant, anti-inflammatory, and anticancer properties and modulates processes like apoptosis, autophagy, and the Warburg effect in cancer cells.

1. MELATONIN
BIOSYNTHESIS
SECRETION AND METABOLIC
MODE OF ACTION
PREPARED BY
MANIKANDAN G
2nd Msc Zoology
JAMAL MOHAMED COLLEGE, TRICHY.

2. INTRODUCTION TO MELATONIN
 Melatonin is regarded as THE DARKNESS HORMONE as it
is synthesized and secreted into the blood predominantly
during DARK.
 Melatonin is synthesized and secreted into the blood
predominantly by the pineal gland[also regarded once as
the THIRD EYE] which is located deep in the middle of
the brain in the thalamus region.
 It is also to be noted that although melatonin is
synthesized in almost every cells of the body, only the
pineal melatonin is the one which is secreted into the
bloodstream during night.
 The melatonin that is synthesized in response to
darkness can exert a feedback over an important
structure in the brain named “THE SUPRACHIASMATIC
NUCLEUS” of hypothalamus the master clock of our
human body which regulates the circadian clock.
 Melatonin also have numerous cellular level effects as
well as its antagonizing effects on reproductive
structures is also well studied.

3. SYNTHESIS OF MELATONIN

4. BIOSYNTHESIS OF MELATONIN
 MELATONIN is derived from the amino acid precursor
TRYPTOPHAN an essential amino acid {Note : Plants
can synthesize TRYPTOPHAN via shikimic acid
pathway}
 In the above pathway mentioned in the figure the
conversion of serotonin to N acetyl serotonin is
regarded as the ‘RATE LIMITING STEP IN THE
BIOSYNTHESIS OF MELATONIN’ as this step is the one
which determines whether melatonin will be
synthesized or not.
 THE ENZYME “SEROTONIN N ACETYL
TRANSFERASE[NAT]” is up regulated or activated only
in the night when the signal is dark.

5. ROLE OF SUPRACHIASMATIC NUCLEI IN
MELATONIN AND SECRETION
 Most, if not all, living cells in plants and animals have
rhythmic fluctuations in their function on a circadian cycle.
Normally they become entrained or synchronized to the
day-night cycle in the environment.
 If they are not entrained, they become progressivley more
out of phase with the light dark cycle because they are
longer or shorter than 24h.
 In most cases, the SUPRACHIASMATIC NUCLEI [SCN] play a
major role in the entrainment process. The SCN receive
information about the light dark cycle via a special neural
pathway , the retinohypothalamic tract .
 Efferent fibers from the SCN initiate neural and humoral
signals that entrain a wide variety of well known circadian
rhythm including the sleep-wake cycle and melatonin
release from the richly vascularized pineal gland

6. ROLE OF SUPRACHIASMATIC NUCLEI

7. SECRETION OF MELATONIN
 Light signals are perceived by a special group of cells in
the retina named “iPRGCs” that is INTRINSCIALLY
PHOTOSENSITIVE RETINAL GANGLIONIC CELLS Which
contains an important pigment called MELANOPSIN.
 Light signals are relayed via the RetinoHypothalamic
Tract {RHT} FIBERS TO THE SCN.
 GABAergic neurons in the SCN inhibit neurons in the
hypothalamic Paraventricular nucleus [PVN] which then
reduces the activity of sympathetic preganglionic
neurons in the spinal intermediolateral nucleus[IML].
 These sympathetic preganglionic neurons innervate
postganglionic neurons in the SUPERIOR CERVICAL
GANGLION (SCG) that regulate the synthesis and
release of melatonin from the pineal gland.

8.  SO, During day as the light strikes iPRGCs, melanopsin gets
stimulated and signals are transmitted via RHT TO SCN, from
SCN inhibitory signals are send to the pineal gland.
 During night this inhibitory signals are transmitted ,as a result
superior cervical ganglion releases norephinephrine to
pinealocytes.
 Norephinephrine stimulates GPCR on pinealocytes membrane
which are coupled to G proteins which then stimulates adenylyl
cyclase to drive cAMP formation, which activates PROTEIN
KINASE A [PKA] which adds phosphates to proteins to activate
downstream events.
 PKA phosphorylates CREB[cAMP RESPONSE ELEMENT BINDING
PROTEIN] which then enters nucleus to transcribe N Acetyl
transferase which catalayses the rate limiting step in the
synthesis of melatonin.

10. MELATONIN : MECHANISM OF ACTION
 Now the synthesized melatonin is from the pineal gland into
blood and CSF
 MELATONIN can then feedback on the suprachiasmatic nucleus
and makes its activity go down.
 Melatonin has two receptors MT1 AND MT2 found on SCN
NEURONS.
 Binding of melatonin to MT1 causes level of cAMP to go down
and initiates sleeping.(MT1 is a GPCR which is has Gi alpha
subunit which when activated inhibits adenylyl cyclase)
 Binding of melatonin to MT2 initiates phosphoinositol hydrolysis
which can synchronize light dark cycle.( MT2 is also GPCR
coupled to Gq alpha subunit)

11.  SCN and most cells have a molecular CLOCK gene regulatory
mechanisms by which 24 hour circadian cycle is regulated.
 These clock genes constitute a circuit called TTFL that is
Transcriptional Translational Feedback LOOP.
 The molecular mechanisms of this TTFL is elucidated which won
the 2017 Nobel prize for physiology.[Advanced info on this
mechanisms are given at end reference links]
 The exact mechanism by which melatonin interferes with this
TTFL Is yet to be discovered, but it is thought that the
decreased cyclic AMP can interfere with TTFL and downregulate
certain clock genes and induce sleep.

13.  Melatonin and its antagonizing role in reproductive structures is well
understood in animals especially in seasonal breeders.
 For example Hamsters are seasonal breeders which breed usually during
summer spring season.
 During winter in which 13 hours of darkness predominates , melatonin
antagonizes Gonadotropin releasing hormone and the gonads are
inhibited and even involuted.
 After 4 months of dysfunction the level of darkness goes down such that
Gonadotropin releasing hormone can overcome the inhibiting effects of
melatonin and the breeding can be initiated during specific seasons.
 Role of melatonin on human reproductive structures remain unclear.
 It is known that high levels of melatonin can delay puberty in pre pubertal
children.
 And abnormal melatonin levels in females are also associated with
irregular menstrual cycle.
 Melatonin receptors are also found in Leydig cells in mammals.

14. CELLULAR ACTIONS OF MELATONIN
 Melatonin has excellent ANTIOXIDANT PROPERTIES.
 Actually melatonin is synthesised in mitochondria.
 It is hypothesized that melatonin actually has endosymbiotic
origin. THAT MEANS PLANTS ALSO CAN SYNTHESIZE
MELATONIN AND PLANTS CAN PRODUCE MORE LEVELS THAN
ANIMALS!![Very recently the very first melatonin receptor in
plants was discovered in Arabidopsis]
 So cells apart from pinealocytes will not release their
melatonin, actually these cells use the melatonin to protect
them from free radicles generated from mitochondiral ETC.
 FREE RADICLES can wreak havoc inside the cell , so it should
be scavenged very efficiently.
 Melatonin can directly scavenge on these free radicles or
indirectly it can increase the activity of free radicle scavanging
enzymes like glutathione peroxidase, superoxide dismutase
etc.

16.  Melatonin has anti inflammatory properties also.
 Melatonin is also known to modulate two important cellular
processes APOPTOSIS AND AUTOPHAGY.
 AUTOPHAGY is a super interesting process in which a cell eats
itself[self eating] to recycle contents when the cells are starving,
this process involves atleast 30 proteins. During this process a
transient DOUBLE MEMBRANE STRUCTURE KNOWN AS
AUTOPHAGOSOME IS FORMED. (Detailed molecular mechanism of
autophagy info is given in reference links)
 It is shown that melatonin can modulate its effects on apotosis
and autophagy depending upon cells condition, but the exact
mechanism remains to be elucidated.

17.  Melatonin has anticancerous effects as well.
 It is shown that it can reverse the WARBURG EFFECT.
 WARBURG EFFECT is one of the hallmarks of cancer cells ,
in which there is a shift from oxidative phosphorylation to
aerobic glycolysis which provides the cancer cells with
many advantages like instant energy , production of
lactate which facilitates metastasis.
 So this effect can be reprogrammed by melatonin. The
detailed description of the research is given in below link
for further reading.
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828708/
#:~:text=Melatonin%2C%20by%20directly%20or%20indi
rectly,the%20stabilization%20of%20HIF%2D1%CE%B1

18. MELATONIN AND WARBURG EFFECT

20. REFERENCE BOOKS AND LINKS
 https://www.nobelprize.org/prizes/medicine/2017/advan
ced-information/
 https://www.nobelprize.org/prizes/medicine/2016/advan
ced-information/
 BOOKS : 1. GANONGS REVIEW OF MEDICAL
PHYSIOLOGY(26TH EDITION)
 2. GUYTON AND HALL TEXTBOOK OF MEDICAL
PHYSIOLOGY(13TH EDITION)