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\begin{document}

\title{Revealing Melatonin's Mysteries: Receptors, signaling pathways, and
therapeutics applications}



\author[1]{Kulsoom Kulsoom}%
\author[2]{Wajahat Ali}%
\author[3]{Zainab Saba}%
\author[4]{Shabab Hussain}%
\author[5]{Muhammad Yasin}%
\author[6]{Samra Zahra}%
\author[7]{Maria Irshad}%
\author[8]{Muhammad  Ramzan}%
\affil[1]{Bahauddin Zakariya University}%
\affil[2]{Xi'an Jiaotong University School of Basic Medical Sciences}%
\affil[3]{Khwaja Fareed University of Engineering \& Information Technology}%
\affil[4]{University of Messina}%
\affil[5]{University of Baltistan}%
\affil[6]{COMSATS University Islamabad - Islamabad Campus}%
\affil[7]{University of Trieste}%
\affil[8]{The Islamia University of Bahawalpur Pakistan}%


\vspace{-1em}



  
  \date{June 17, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Melatonin (5-methoxy-acetyl tryptamine) sleep-inducing hormone, and the
pineal gland produces it in response to the circadian clock of darkness.
In the body, MT1 and MT2 receptors are mostly found, having an
orthosteric pocket and ligand binding determinants. Melatonin acts by
binding on melatonin receptors, intracellular proteins, and orphan
nuclear receptors. It inhibits adenyl cyclase and activates
phospholipase C, resulting in gene expression and an intracellular
alteration environment. Melatonin signaling pathways are also associated
with other intracellular signaling pathways, i.e., cAMP/PKA and MAPK/ERK
pathways. Relative expression of different proteins depends on the
coupling profile of G protein, accounting pharmacology of the melatonin
receptor bias system, and mediates action in a Gi-dependent manner. It
shows antioxidant, antitumor, antiproliferative and neuroprotective
activity. Different types of melatonin agonists have been synthesized
for the treatment of sleeping disorders. Researchers have developed
therapeutics that target melatonin signaling, which could benefit a wide
range of medical conditions. This review focuses on melatonin receptors,
pharmacology, and signaling cascades; it aims to provide basic
mechanical aspects of the receptor's pharmacology, melatonin functions
in cancer and neurodegenerative diseases, and any treatments and drugs
designed for these diseases. This will allow a basic comparison between
the receptors in question, highlighting any parallels and differences
that may exist and providing fundamental knowledge about these receptors
to future researchers.%
\end{abstract}%



\sloppy


\textbf{Revealing Melatonin's Mysteries: Receptors, signaling pathways,
and therapeutics applications}

Kulsoom\textsuperscript{1}, Wajahat Ali\textsuperscript{2} ,Zainab
Saba\textsuperscript{3}, Shabab Hussain\textsuperscript{4}, Muhammad
Yasin\textsuperscript{5} Samra Zahra\textsuperscript{6}, Maria
Irshad\textsuperscript{7}, Muhammad Saeed Ramzan\textsuperscript{8}

\textsuperscript{1}Department of Biochemistry, Bahauddin Zakariya
University Multan, Pakistan https://orcid.org/0009-0003-9146-3069,
kalsoomsana45@gmail.com

\textsuperscript{2}School of Basic Medical Sciences, Xian Jiaotong
University, China, https://orcid.org/0009-0008-5716-0597,
aliwajahat@stu.xjtu.edu.cn

\textsuperscript{3}Department of Optometry, Khawaja Fareed University of
Engineering \& Information Technology, Rahim Yar Khan, Pakistan
https://orcid.org/0009-0004-3345-1569, zainabsaba34@gmail.com

\textsuperscript{4}University of Messina Italy,
Shabab.hussain@studenti.unime.it, https://orcid.org/0000-0002-2537-4792

\textsuperscript{\textbf{5}} Department of Zoology, University of
Baltistan Skardu, Pakistan, yasin@aup.edu.pk

\textsuperscript{6}Department of Biosciences, COMSATS University
Islamabad, Pakistan, samrazahra6@gmail.com

\textsuperscript{7}University of Trieste, Italy, Department of Medical,
Surgical and Health Sciences MARIA.IRSHAD@phd.units.it

\textsuperscript{8}Department of Pharmacology, Islamia University
Bahawalpur, Pakistan,https://orcid.org/0009-0005-9243-0028,
dr\_msramzan@yahoo.com

\textbf{Abstract:} Melatonin (5-methoxy-acetyl tryptamine)
sleep-inducing hormone, and the pineal gland produces it in response to
the circadian clock of darkness. In the body, MT1 and MT2 receptors are
mostly~found, having an orthosteric pocket and ligand binding
determinants. Melatonin acts by binding on melatonin receptors,
intracellular proteins, and orphan nuclear receptors. It inhibits adenyl
cyclase and activates phospholipase C, resulting in gene expression and
an intracellular alteration environment. Melatonin signaling pathways
are also associated with other intracellular signaling pathways, i.e.,
cAMP/PKA and MAPK/ERK pathways. Relative expression of different
proteins depends on the coupling profile of G protein, accounting
pharmacology of the melatonin receptor bias system, and mediates action
in a Gi-dependent manner. It shows antioxidant, antitumor,
antiproliferative and neuroprotective activity. Different types of
melatonin agonists have been synthesized for the treatment of sleeping
disorders. Researchers have developed therapeutics that target melatonin
signaling, which could benefit a wide range of medical conditions. This
review focuses on melatonin receptors, pharmacology, and signaling
cascades; it aims to provide basic mechanical aspects of the receptor's
pharmacology, melatonin functions in cancer and neurodegenerative
diseases, and any treatments and drugs designed for these diseases. This
will allow a basic comparison between the receptors in question,
highlighting any parallels and differences that may exist and providing
fundamental knowledge about these receptors to future researchers.

\textbf{Graphical Abstract:}

\textbf{Keywords:} Melatonin Hormone, Synthesis of Melatonin, Mechanism
of Melatonin, Melatonin Receptors, Receptor Structure, Receptor
Signalling cascades/pathways, Therapeutic Application

\textbf{Word count:} 4843

\textbf{Abbreviations}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{MT1} \textbf{MT2} \textbf{GPCRs.} \textbf{IP3} \textbf{PLCB}
\textbf{PI3K} \textbf{Bcl2} \textbf{B-ARR} \textbf{Bax} \textbf{cGMP}
\textbf{sGC} \textbf{PKG} \textbf{CREB} \textbf{cAMP} \textbf{SIRT}
\textbf{ROS} \textbf{PDK} \textbf{Akt} \textbf{hMT1/hMT2} \textbf{PKC}
\textbf{MEK1/2} \textbf{ERK 1/2} \textbf{SIRT1/2} \textbf{Nrf2}
\textbf{PGC-1a} \textbf{Nf-kB} \textbf{Gi} \textbf{Gq} \textbf{GLUT1}
\textbf{LPS} \textbf{SOD1/2} \textbf{ECL2} \textbf{HEK} \textbf{COS 7}
\textbf{PACAP} \textbf{mPer1} \textbf{mCry1} \textbf{Bmal 1} \textbf{ES}
& Melatonin type 1 receptors Melatonin type 2 receptors G-protein
coupled receptors Inositol trisphosphate Phospholipase C Beta
Phosphoinositol 3 kinase B-cell leukemia/lymphoma 2 protein. Beta
adrenergic receptors Bcl-2-associated X protein Cyclic guanosine
monophosphate Soluble guanylate cyclase Protein kinase G cAMP-response
element binding protein Cyclic adenosine monophosphate Selective
internal radiation therapy Reactive oxygen species Protein D kinase Ak
strain transforming(serine/threonine kinase 1) Human melatonin type 1
receptors/Human melatonin type 2 receptors Protein kinase C
Mitogen-activated protein kinase kinase Extracellular signal-regulated
kinase Sirtuin histone deacetylase1/2 Nuclear factor erythroid 2-related
factor 2 Peroxisome proliferator-activated receptor-gamma coactivator
Nuclear factor kappa B G-inhibitory protein Guanine nucleotide binding
protein Glucose transporter type 1 Lipopolysaccharides Superoxide
dismutase 1/2 Extracellular Loop 2 Human embryonic kidney 293 cells
Cellosaurus COS-7 Pituitary adenylate cyclase-activating polypeptide
mPeriod 1 gene in suprachiasmatic nucleus Mouse cryptochrome genes 1
(Brain and muscle arnt(Arylhydrocarbon Receptor Nuclear
Translocator)-Like Protein Embryonic stem cells\tabularnewline
\bottomrule
\end{longtable}

\textbf{1. Introduction:}

Melatonin, chemically 5-methoxy-acetyl tryptamine, is a sleep-inducing
hormone, and in 1958, it was extracted from a pineal gland (Lerner et
al., 1958). Its concentration is high at night time in all species.
Animals' endogenous circadian clock, which secretes the hormone
melatonin at night, is synchronized by light and dark cycles in the
suprachiasmatic nucleus of the hypothalamus. In a 24-hour cycle, the
pineal gland releases the hormone melatonin. When the retina detects
stimuli of darkness, it is perceived by the suprachiasmatic nucleus,
which generates a signal in the form of a nerve impulse and sends it to
the upper thoracic cord of the intermediolateral column, then perceived
by the superior cervical ganglion. After adrenergic stimuli, pinocytes
of the pineal gland synthesize the melatonin hormone intracellular.
Neurological and physiological processes are regulated by melatonin.
Photoperiodic species show seasonal changes regulated by the melatonin
hormone in the hypothalamus, the pituitary pars tuberalis. It exerts
direct action on the suprachiasmatic nucleus and entrains the circadian
clock.

Circadian rhythm disorders, i.e., jet lag, shift work, blindness, and
delayed or advanced sleep phase syndromes, are treated by the response
exerted by the melatonin hormone (Hagan \& Oakley, 1995). Dopamine
synthesis is repressed from the retinal amacrine cells by melatonin (A.
S. L. Chan et al., 2002) and can promote vasoconstriction in the rat
tail artery (Brydon et al., 1999). Melatonin has also played a
well-established hypnotic action (Kr\selectlanguage{ngerman}äuchi et al., 2000). It triggers the
opening of the sleep gate, which is circadian-dependent and initiates
sleeping (Kräuchi et al., 2000) . Melatonin meditates action as an
antioxidant and influences immune function. Sleep and wake rhythm are
induced by melatonin (Reppert et al., 1994). The physiological
processes, such as regulating the cardiovascular system, are controlled
by melatonin (Reppert et al., 1995) and buffering of the immune system
and neurodegenerative disorders (Dubocovich et al., 2010). In drug
designing, the therapeutic agents are designed that target melatonin
targets. Melatonin plays a role in cancer protection, confirmed by
research, bone formation glucose maintenance (Sewerynek, 2002).

\textbf{2. Synthesis of Melatonin hormone:}

The synthesis of melatonin involves a two-step process from the pineal
gland;

Arylalkylamine is used for serotonin acetylation by using
acetyltransferase enzyme to produce acetylserotonin,

Melatonin is synthesized by the enzyme hydroxy
indole-O-methyltransferase by methylation of the 5-hydroxy group.

\textbf{3. Excretion of Melatonin:}

Mainly in the liver, melatonin is metabolized most efficiently but to
some extent in the kidney. Melatonin is oxidized into 6-hydroxy
melatonin in the liver by the cytochrome P 450 enzyme, and 6-hydroxy
melatonin is then conjugated with sulphuric acid to 6-sulfatoxymelatonin
(Tan et al., 2015). In the form of 6-sulfatoxy-melatonin, it is
eliminated from the body through urination, which is a major melatonin
metabolite used to access melatonin concentration in the plasma (Lynch
et al., 1975).

\textbf{Figure 1:}

\textbf{4. Mechanism of Melatonin effects:}

In mammals, the effects of melatonin are revealed by four different
mechanisms;

1. Melatonin acts as an antioxidant

2. Melatonin binds to plasma membrane receptors

3. Interaction of melatonin to intracellular proteins, i.e., calmodulin

4. Orphan nuclear receptors are targeting (Ekmekcioglu, 2006)

Intracellular proteins, i.e., calmodulin, calreticulin, and tubulin,
interact with melatonin (Pandiperumal et al., 2008). The binding of
calcium to calmodulin, an intracellular second messenger, is antagonized
by melatonin (Ekmekcioglu, 2006; Pandiperumal et al., 2008). Showed
regulation of antiproliferative effects in cancer. Melatonin shows
immunomodulatory effects, which is mediated by retinoid-related Orphan
nuclear receptor. Mononuclear cells secrete interleukins IL-2 and IL-6
owing to this modulation (Ekmekcioglu, 2006).

\textbf{Figure 2:}

\textbf{5. Melatonin receptors:}

Melatonin receptors present on the plasma membrane of different cells,
i.e., cells of the immune system, cells of the coronary artery, cells of
the cardiac ventricular wall, cells of the cardiovascular system,
appendix vermiform, hepatocytes, gallbladder, duodenal enterocytes,
aorta cells of the large intestinal cecum, colon, skin cells, fetal
kidney, kidney, platelets, brain, retina, parotid gland, cells of
cerebral arteries, exocrine pancreas, breast and prostate epithelial
cells, placenta, epithelial cells of breast, cells of the ovary,
myometrium, brown adipocytes, white adipocytes are morphology different
from each other's (Tan et al., 2016; Uz et al., 2005). Jejunal and
colonic mucosal cells possess melatonin receptors (Pandiperumal et al.,
2008). Melatonin Receptors are of four different types in living
organisms in different cells. Three receptors are on the plasma
membrane, while one is the nuclear receptor.

\textbf{5.1. Type 1a receptor:} These are primarily present in human
skin cells, consisting of 351 amino acids and encoded by a gene on
chromosome\#4. It has five different receptor subtypes, i.e., MT1,
MTNR1A, Mel1a, ML1a, and ML1 (Li et al., 2013). The binding of type 1
melatonin receptors to different types of GPCRs inactivates Adenyl
cyclase (López-Canul et al., 2015). These receptors' expression is
decreased in the cortex and suprachiasmatic nucleus during Alzheimer's
and aging (Pandiperumal et al., 2008), suppressing protein secretion and
neuronal discharge in the suprachiasmatic nucleus (Dubocovich, 2003).

\textbf{5.2. Type 1b receptor:} The gene for this receptor is present on
chromosome\#11, encoding a polypeptide of 363 amino acids. It has three
different receptor subtypes, i.e., MTNR1B, ML1b, and MT2 (Li et al.,
2013). The binding of this receptor to different GPCRs inactivates
Adenyl cyclase and guanylyl cyclase (López-Canul et al., 2015). cAMP
synthesis is decreased by inactivating adenyl cyclase (Chaste et al.,
2011). These receptors are located in sweat glands and malign
melanocytes (Pandiperumal et al., 2008). These receptors inhibit gamma
amino butyric acid A receptors in rat hippocampus (Dubocovich, 2003).
Showing antidepressant properties reveals that their expression
decreased in Alzheimer's disease (Tan et al., 2016), depression \& sleep
diseases are associated with abnormal melatonin receptors, and
pharmacology and Pathophysiology of Alzheimer's \& anxiety diseases are
associated with abnormality in these receptors. These receptors are the
new target for hypotonic agents. Anxiety and sleep cycles are regulated
by these receptors. MT1/MT2 doesn't possess hypotonic effects as
compared to these receptors (López-Canul et al., 2015).

\textbf{5.3. MTNR1C \& Mel1c:} These receptors are present in fish,
birds, and amphibians but not in humans. The chicken MT1 and MT2
receptors are antagonistic to this receptor's circadian rhythm. In the
daytime, it is present in high and low concentrations at night (Li et
al., 2013).\textbf{5.4. MT3:} This receptor shows antioxidant properties
due to the Quinone reductase-2 enzyme and inhibits the electrons
transfer reaction of Quinone (Pandiperumal et al., 2008). Melatonin type
3 receptors and detoxification Quinone reductase 2-enzyme are present on
the plasma membrane of muscle, brown fat tissue, liver, kidney, heart,
lung, and intestinal cells. Intraocular pressure is regulated by it
(Ekmekcioglu, 2006).\selectlanguage{greek}\textbf{5.5. RZR/RORα:} \selectlanguage{english}These nuclear receptors help
bind melatonin to transcription factors in the nucleus and belong to the
retinoic acid receptor super T family (Hazlerigg \& Loudon, 2008). This
receptor consists of 618 amino acids encoded by chromosome\#28 (Li et
al., 2013). This receptor doesn't bind to melatonin and is present in
all mammals (Ekmekcioglu, 2006); it helps bind melatonin to MT
(Hirsch-Rodriguez et al., 2007).

\textbf{5.6. Table:1}

\textbf{6.1 Melatonin type 1 and type 2 structure signaling complex:}

2-iodomelatonin, a nonselective agonist (Dubocovich et al., 2010) \&
ramelteon (Kato et al., 2005) are used to obtain stable MT1 Gi-Protein
complexes. Both of these compounds show high potency and affinity toward
these receptors. Co-expression of G protein and receptor was studied in
the insect cells. The resolution of 2-iodomelatonin and ramelteon was
determined, showing global resolutions 3.1 and 3.3 \selectlanguage{ngerman}Å, respectively. The
assembled complex was purified for homogeneity, and cryo-EM studied
their complexes for single particles. An atomic model consisting of
ligands MT1, Gi, and scFv1627 was built, and relatively high-quality
density maps were used. The side chain of melatonin receptor type 1 and
G-inhibitory protein was explained in the structure. TM1 and TM7 possess
extra density between their N-terminal portions, and as a cholesterol
molecule, it was changed. The agonist-bound MT2-Gi complex was studied
in the same manner. The reconstituted ramelteon-bound MT2-Gi-scFv16
complex was acquainted by cryo-EM.

\textbf{Figure 3:}

For high-resolution maps, the receptor stability was improved. According
to previous findings, three thermostable mutations, F1293.41W,
C1403.52L, and L108ECL1F , were introduced to MT2, which are not
contagious to the coupling interface of G-protein and ligand binding
pocket. The ligand interaction with receptor and G-proteins coupling
interferes minimally with mutations (Johansson et al., 2019). An EM
density map was obtained at 3.5 nominal resolution by using the triple
mutant complex of ramelteouun-MT2-Gi-scFv16, enabling to model
ramelteon, scFv16, significant portions of the receptor, MT1 and MT2 Gi
protein receptors are assembled similarly to Gi protein, GPCRS, and
G-protein complexes. The ramelteon and 2-iodomelatonin ligands bound to
orthostatic pockets of MT1 and MT2 receptors. MT1-Gi bound to ramelteon
bound and 2-iodomelatonin are structurally identical, showing 1 A° root
mean square deviation values indicating complexes of Ca atoms and 0.8 Å
values indicating the Ca atoms of MT1. Ramelteon-bound MT2-Gi and MT1-Gi
are structurally identical showing 1.4 roots mean square deviation of
receptors Ca. The regions involved in the engagement of G-protein and
the extracellular side are structurally different.

\textbf{6.2 Ligand Selectivity Determinants and Orthosteric:}

The orthosteric pocket created by TM3, TM5, TM6, TM7, and ECL2 in the
structures of both MT1 and MT2 binds ramelteon and 2-iodomelatonin.
(Fig. 4a, c). It is possible to superimpose the ramelteon's binding pose
with that of inactive structures in active MT1 or MT2. But the active
form of 2-iodomelatonin changes slightly from the inactive form,
especially where the alkyl amide tail is concerned, where it approaches
the W6.48 residue in functioning MT1, which acts as a ''toggle switch.''
ECL2 consistently occupies the pocket's top position in both
conformations, blocking ligand accessibility through the extracellular
side (Fig. 4b, d). The only access point to the orthosteric-binding site
in the active conformation has been discovered to be the lateral channel
between TM4 and TM5. It was discovered that the only access point to the
orthosteric-binding site in the active conformation is the lateral
channel between TM4 and TM5. (Fig. 4b, d) The orthosteric pocket is more
constrained in the center of active structures, but TM3, TM4, and TM5 in
dormant structures make a large ''longitudinal channel'' that this fiber
bundle grows to join. While the residues around the iodine group and
alkyl amide tail (referred to as the R3 position in melatonin, Fig.5)
match up well, the active pocket's structure might vary depending on the
conformations of the residues flanking the solvent channel (Fig. 4e, f).
A hydrogen bond is formed between the aromatic residue Y1875.38 in MT1
and N1624.60 in the active structure by rotating from the inactive
structure's solvent-facing conformation toward TM4.

Furthermore, the hydrogen bond's diameter of the ligand entry is
decreased, which may inhibit the unbinding of the bound agonist because
the Y1875.38A mutation caused a high ligand dissociation rate. The
functional relevance of this proton pair in MT1 activation was further
demonstrated by the fact that the N1624.60A mutation rendered MT1
inactive. Homologous pair N1754.60 and Y2005.38 also underwent
structural changes in MT2 during the transition. This hydrogen bond's
absence demonstrates that MT2 does not require an entrance-restricting
hydrogen bond similar to the one found in MT1 for activation, which is
consistent with the earlier finding that the N1754.60 protein does not
need such a hydrogen bond (Stauch et al., 2019). No functional
consequences resulted from a mutation (Johansson et al., 2019). Because
N4.60-Y5.38 can be altered in conformation thanks to a conserved proline
(P4.59) located close by in MT1 and MT2, changing P4.59 impairs MT2's
ability to bind ligands (Mazna et al., 2008).

Residue H5.46 (H1955.46 in MT1 and H2085.46 in MT2), two helical turns
beneath Y5.38, distinguishing the pockets most clearly from the active
and dormant structures (Fig. 4e, f). The pocket size of the residue
H5.46 (H1955.46 in MT1 and H2085.46 in MT2) differs the most between the
inactive and active forms (Fig. 4e, f). H5.46 avoiding bound ligand
forms inactive complexes with TM4 (Fig. 4e, f). The toggle switch
residue W6.48 (W2516.48 in MT1 and W2646.48 in MT2) and van der Waals
contacts with the connected ligand's alkyl amide tail are formed when
the ligand moves inside by 2.4 angstroms and flips its side chain in the
active structures (Fig. 4e, f). H5.46's new conformation clarifies why
the H2085.46A mutation dampened MT2 activity (Hagan \& Oakley, 1995;
Johansson et al., 2019).

Despite the fact that H5.46 experiences similar conformational changes
in MT1 and MT2, its functional significance seems to vary between the
two receptors, as the H2085.46 (MT2) mutation only slightly decreased
MT2 function whereas the H1955.46A (MT1) mutation drastically impaired
MT1 activity. Then, we docked to both receptors using the common ligands
CTL 01-05-B-A0527 and 5-hydroxyethoxy-N-acetyltryptamine (5-HEAT) (Nonno
et al., 2000). In contrast to melatonin, 5-HEAT and CTL 01-05-B-A05 have
substitutions in the R1 position. 5-HEAT was able to keep a position
superimposable to that of bound 2-iodomelatonin thanks to hydrogen bonds
to MT1 residues N1624.60 and Y1875.38. (Fig. 4g). To conclude that
5-HEAT is an MT1 agonist, we must first determine whether or not its
molecular structure is consistent with the expected position of the
active pocket necessary to activate MT1.

On the other hand, due to the dissimilar shapes of N1754.60 and
Y2005.38, the MT2 antagonist 5-HEAT was not a good fit for docking in
the active pocket of MT2. Induced-fit binding is probably used by
5-HEAT. Weak binding of CTL 01-05-B-A05 to MT2 was observed because the
side chain of I2075.45 disrupted the stacking contact between these two
molecules. (Fig. 4i). Notably, in light of our findings, further biopic
ligand development is required to produce more focused MT1 agonists. In
light of our findings, further development of the biopic ligand is
required to produce more focused MT1 agonists. A feasible technique for
optimizing the fit with the ''longitudinal channel'' would include
specific substituents in the second unit.

\textbf{Figure 4:}

The region known as the sub-pocket, which is located around the R3 group
of the ligand and was barely distinguishable in the inactive MT1 and MT2
pockets, became more distinct in the active structures. At position 7.40
in MT1, there is a tyrosine (Y2827.40). Lucien (L2957.40) is the
equivalent residue in MT2 (Fig. 5j). When Y2827.40 is packed against
TM1, the two adjacent residues Y2817.39 and Y2857.43 are pushed closer
to the pocket's center than the corresponding residues Y2947.39 and
Y2987.43 in MT2 (Fig. 4j). Since MT2 has a larger sub pocket; as a
result, it can accommodate ligands with bulky R3 substituents, which is
in line with the chemical architectures of the majority of MT2 selective
agonists. (K. H. Chan et al., 2020; Zlotos et al., 2014). MT1 and MT2
receptors are structurally and functionally similar and also have unique
features in their ligand binding pockets. The N4.60-Y5.38-H5.46 motif,
the longitudinal channel, and the larger subpocket in melatonin receptor
type 2 could all be used as targets for the designing~of melatonin
subtype-selective drugs.

\textbf{Figure 5:}

\textbf{7.1. Receptor signaling:}

The intrinsic melatonin receptor affinity for different types of G
proteins is not yet known. The relative expression of different proteins
is dependent on the coupling profile of the G protein, accounting
pharmacology of the melatonin receptor bias system. MT1 and MT2
receptors inhibit Adenyl cyclase after coupling to G inhibitory
proteins. Melatonin receptor type 1 co-immunoprecipitated with G\selectlanguage{greek}α\selectlanguage{english}i3 and
G\selectlanguage{greek}α\selectlanguage{english}i2 inhibitory proteins, has the least affinity for Gq/11 proteins and
doesn't couple to G\selectlanguage{greek}α\selectlanguage{english}i1, G\selectlanguage{greek}α\selectlanguage{english}z, G\selectlanguage{greek}α\selectlanguage{english}o, G\selectlanguage{greek}α\selectlanguage{english}12, or G\selectlanguage{greek}α\selectlanguage{english}s proteins in HEK293 cells
(Brydon et al., 1999). G\selectlanguage{greek}α\selectlanguage{english}16 protein is expressed in hematopoietic cells,
which illustrates the bias system (Amatruda et al., 1991). Melatonin
receptors type 1 and type 2 couple to G\selectlanguage{greek}α\selectlanguage{english}16 protein through Jun
N-terminal kinase. In COS-7 cells, the melatonin signaling pathway is
initiated (A. S. L. Chan et al., 2002). The concentrations of inositol
triphosphate, diacylglycerol, Ca2+, and cAMP are regulated by melatonin
receptors in the cells (Brydon et al., 1999). In tissues and cells,
Gq/11 couples to melatonin receptors endogenously in the myometrium,
prostate (Steffens et al., 2003), pancreatic cells and epithelial cells
(B\selectlanguage{ngerman}ähr et al., 2012) and mesenchymal stem cells of humans (Lee et al.,
2014), cells from non-mammalian organisms (Hotta et al., 2000) and cells
which express recombinants (MacKenzie et al., 2002). Ion channels and
multiple pathways are regulated by melatonin. Muscle contraction is
modulated by melatonin in arteries (Masana et al., 2002). Melatonin
controls the myometrium's conductance of K+ channels that Ca2+
activates, and the activation of the Gi/cAMP/PKA \& Gq/PLC/Ca2+
signaling pathways modulates the function of these channels. Activation
of gene transcription \& inhibition of transcriptional factor cAMP
responsive element binding protein takes place through
extracellular-signal-regulated kinase pathway at the transcriptional
level. Melatonin receptors type 1 and type 2 are different only in the
inhibition of cGMP synthesis during signaling. Melatonin receptor type 2
synthesizes cGMP, which is studied in human non-pigmented ciliary
epithelial cells (Petit et al., 1999).

\textbf{7.2. Signalling cascades and Effects:}

Regulation of circadian rhythm has been extensively studied and based on
system bias (Dubocovich et al., 2010). Melatonin affects the master
clock and hypothalamic suprachiasmatic nucleus neurons and mediates in a
cAMP-independent manner but a Gi-dependent manner. G protein-coupled
receptors are activated, rectifying K-channels, i.e., Kir3 in melatonin
receptors type 1 (Nelson et al., 1996), and melatonin receptor type-2
mediates action through the PKC signaling pathway (McArthur et al.,
1997). Both receptors modulate neuronal actions through induced cAMP
synthesis by pituitary Adenyl cyclase activating peptides (PACAP) in the
suprachiasmatic nucleus (Pfeffer et al., 2012). Melatonin mediates
action in a Gi-dependent manner and modulates gene expression in the
striatum (Imbesi et al., 2009). Melatonin type 1 receptor can affect the
rate of activation of cerebellar Purkinje cells by inhibiting P-type
Ca2+ channels via Gi/G/PI3K/PKC signaling (Zhang et al., 2015).
Synchronizing effects in the hypophyseal pars tuberalis with SCN are
mediated by melatonin. In order to control the production of mPer1,
mCry1, clock, and Bmal1 genes, melatonin activates a heterologous
repressive mechanism via MT1 and adenosine A2B receptors and sensitizes
the cAMP pathway (Von Gall et al., 2002). This signaling cascade is
mediated by NPAS4, a transcription factor with a Per-Arnt Sim domain,
and G protein regulators (West et al., 2013). It is not fully understood
how melatonin regulates circadian rhythm, but it appears to vary on cell
type (Mühlbauer et al., 2009), including Clock Gene Transcription and
Post-Translational Regulation (Vriend \& Reiter, 2015). Melatonin
regulates the clock machinery of the retina. The melatonin signaling
mechanism in retinal physiology is still unknown (Dinet et al., 2007).

\textbf{Figure 6 :}

Melatonin receptors of knockout mice showed variations in the expression
of genes that control clock rhythm and other genes' expression (Hiragaki
et al., 2014). Melatonin mediates action dependent on MT1/MT2
heteromers, activating Gq/PLC/Ca2+ pathway and controlling light
sensitivity in the retina at night (Hiragaki et al., 2014); regulation
of photoreceptor is dependent on the Akt/FOXO1 signaling pathway
(Gianesini et al., 2016). During pathological and physiological
conditions, the viability of neurons is regulated by melatonin.
Melatonin shows neuroprotective and antiapoptotic and different
signaling pathways. Melatonin helps in cell survival, maturation, and
differentiation in the stem cells and is prevented by luz indole, a
competitive receptor antagonist (Ramírez-Rodríguez et al., 2009).
Melatonin stimulates neural development in pluripotent stem cells by
activating the PI3K/Akt pathway, while luz indole inhibits this process
(Shu et al., 2016). Melatonin increases the glucose transporter GLUT1's
activity, activating the PI3K/Akt and ERK pathways in ES cells to
promote pluripotency (X. Wang et al., 2011; H. Wu et al., 2017) Luz
indole is vulnerable to neurons and is the main cause of neuron cell
death in MT1-silenced cells. Melatonin upregulates different antioxidant
enzymes, i.e., SOD1 and glutathione peroxidase, and plays antiapoptotic
and antioxidant roles in ischemia or reperfusion (Parada et al., 2014).
Neuroprotective effects of melatonin and ago melatonin in cerebral
ischemia via up-regulation of nuclear factor erythroid related factor 2
and down-regulation of reactive oxygen species (Ding et al., 2014).
Neu-P11 ligand, which acts on both the 5-HT and melatonin receptors,
activates multiple pathways critical to neuronal survival. These include
the PI3K/Akt, ERK, and JAK2 pathways (Buendia et al., 2015) (Figure\#7).
Mitochondrial function and dynamics are responsible for the antioxidant
and antiapoptotic effects of melatonin (Tan et al., 2016). It activates
caspase-3 and, prevents cytochrome c from being released \& regulates
Bcl-2 and Back expression (Radogna et al., 2008). Bax/Bcl-2
translocation is induced by the JAK2/STAT3 pathway in cardiomyocytes
(Duan et al., 2013). By inducing ERK activation and blocking p38 MAPK in
monocytes, an antiapoptotic effect is produced (Hardeland, 2012).
Sirtuin histone deacetylase (SIRTs) is activated by melatonin through
mitochondrial signaling pathways (Mayo et al., 2017), i.e., In
hepatocytes, AMP-activated protein kinase (AMPK), sirtuin 3 (SIRT3),
superoxide dismutase (SOD2), and sirtuin (Guo et al., 2014). The
transcription factor PGC-1\selectlanguage{greek}α \selectlanguage{english}is controlled by the MT1 receptor in retinal
cells (Kunst et al., 2015). The nuclear factor kappa B (NF-kB) pathway
is inhibited by sirtuin 1 (SIRT1), which in turn causes the
anti-inflammatory effects of melatonin (Tajes et al., 2009).
Melatonin-induced MT1-dependent regulation of mitochondrial function in
mice models is used to treat the neurodegenerative diseases of
Alzheimer's disease, Huntington's disease, and amyotrophic lateral
sclerosis (Li et al., 2013). Cytochrome c is inhibited by melatonin in
brain mitochondria through mitochondrial MT1 receptors (X. Wang et al.,
2011). A cell-permeable melatonin receptor agonist was employed to
distinguish between the mitochondrial Gi/cAMP cascade generated by MT1
and the rest of the cell (Gbahou et al., 2017). Melatonin's
neuroprotective effects are under-studied and is associated with
mitochondrial MT1 signaling pathways. In the cancer field, melatonin
impacts system bias on melatonin receptor cascades and shows antitumor
properties by inducing apoptosis and inhibiting proliferation. MT1
receptors inhibit the phosphorylation of AKT, ERK, and PKC molecules in
breast cancer models and show antitumor activity (Hill et al., 2015). In
these cells, melatonin activates the p53 DNA pathway dependent on the
receptor\textbf{,} Akt, p38 MAPK and mTOR pathways are inhibited by
melatonin in ovarian cancer.

\textbf{Figure 7 :} .

\textbf{8. Therapeutic application:}

The regulatory effects of melatonin on the sleep-wake cycle and
circadian rhythm are crucial for a wide range of melatonin therapeutic
applications. Due to its potential therapeutic effects, melatonin
hormone is used to treat a variety of disorders, including jet lag,
insomnia, circadian rhythm disorders, mood disorders, cancer,
cardiovascular diseases, and neurodegenerative diseases, such as
Alzheimer's disease and Parkinson's disease, as well as other seasonal
affective disorders.

\textbf{Figure 8:}

\textbf{8.1. Cardiovascular system:}

\textbf{8.1.1. Lipids metabolism:} Melatonin reduces high serum total
cholesterol and triglyceride levels in the blood. It improves lipid
metabolism by decreasing low-density lipoprotein and hence maintains
lipid profile (Kozir\selectlanguage{ngerman}óg et al., 2011).

\textbf{8.1.2. Blood Pressure:} Melatonin intake decreases systolic and
diastolic blood pressure at night. It also decreases nocturnal systolic
blood pressure (Borghi \& Cicero, 2017).

\textbf{8.1.3. Ischemia/reperfusion injury:} Consuming melatonin reduces
the severity of cardiac marker injury and myocardial infarction size. It
lowers heart rate by increasing ejection fraction. Melatonin intake
improves blood pressure, glycaemic, and lipid in patients suffering from
chronic heart diseases (Baker \& Kimpinski, 2018).

\textbf{8.1.4. Heart Failure:} Owing to antioxidant and antiapoptotic
properties, melatonin intake decreases cardiac fibrosis in nonischemic
heart failure. Its intake prevents myocardial infarction (Nduhirabandi
\& Maarman, 2018).

\textbf{8.2. Nervous System}

\textbf{8.2.1. Ischemic stroke:} Melatonin intake is helpful in
decreasing infarct volume and brain edema and improving neurologic score
(Liu et al., 2019).

\textbf{8.2.2. Alzheimer's disease:} Melatonin intake is helpful in
improving sleep quality and cognitive function in the brain. Its intake
treats sleep disorders associated with amnesia, sundowning, and
Alzheimer's diseases (Lin et al., 2013).

\textbf{8.2.3. Parkinson's disease:} As it delays the degeneration of
dopaminergic neurons in the substantia nigra, melatonin intake is
beneficial in the treatment of Parkinson's disease. Cognitive
dysfunction, anxiety, depression, and sleep quality all improve as a
result (Medeiros et al., 2007).

\textbf{8.2.4. Epilepsy:} Melatonin improves sleep behavior in epilepsy
patients (Gupta et al., 2004).

\textbf{8.2.5. Migraine:} Melatonin is used to treat migraine and
prophylaxis in both adults and children (Fallah et al., 2015).

\textbf{8.2.6. Chronic tension-type headache:} Melatonin intake improves
sleep quality and prevents headache and tension (A. B. Danilov et al.,
2020).

\textbf{8.2.7. Traumatic brain injury and spinal cord injury:} Melatonin
is used to treat sleep disturbances in patients with traumatic brain
injury who report feeling anxious (Grima et al., 2018).

\textbf{8.3. Reproductive system}

\textbf{8.3.1. Erectile dysfunction:} Consuming melatonin enhances the
corpus cavernosum's ability to contract and relax. It improves
endothelial density and erectile function (Tavukçu et al., 2014).

\textbf{8.3.2. Female reproductive system:} Melatonin intake improves
fertilization rate. It increases progesterone production in the corpus
luteum (Hu et al., 2020).

\textbf{8.4. Gastrointestinal system}

\textbf{8.4.1. Gastroesophageal reflux disease and Gastrointestinal
ulcer:} Melatonin provides protection against mucosa oxidative damage in
different types of gastrointestinal tract ulcers, reduces relaxation
duration, and increases gastrin (Kandil et al., 2010).

\textbf{8.4.2. Irritable bowel syndrome:} Melatonin decreases abdominal
pain, bloating, and constipation and increases rectal pressure
(Chojnacki et al., 2013).

\textbf{8.4.3. Hepatic steatosis:} Melatonin lowers liver cholesterol,
triglycerides, serum AST and ALT levels in hepatic steatosis patients
(Bahrami et al., 2020).

\textbf{8.4.4. Hepatoprotective effects:} Haemorrhagic shock,
ischemia-reperfusion injury, liver damage, ionizing radiation, and
Schistosoma mansoni infection are all diminished by melatonin (Mathes,
2010).

\textbf{8.5. Renal system}

\textbf{8.5.1. Reno protective effects:} Melatonin protects against
radiation-, folic acid-, aminoglycoside-, contrast-mediated-, and
nephrotoxicity-induced by these agents. It reduces creatinine and blood
urea nitrogen levels (Kim et al., 2019).

\textbf{8.5.2 Sepsis-induced renal injury:} Melatonin intake decreases
inflammasome activation (Dai et al., 2019).

\textbf{8.6. Dermatology:} Melatonin protects against UV-light-induced
damage by preventing the production of free radicals, erythema caused by
natural sunlight, and radioprotective effects. It exhibits antiaging
properties, enhances hydration, and lessens the roughness of the skin
(Rusanova et al., 2019).

\textbf{8.7.1. Fibromyalgia:} Melatonin intake improves pain level and
fibromyalgia (A. Danilov \& Kurganova, 2016).

\textbf{8.8.1. Autism spectrum disorder:} Consuming melatonin lowers
mid-sleep awakenings, improves sleep quality, and lengthens total sleep
time (Maras et al., 2018).

\textbf{8.8.2. Mood disorder:} Melatonin diminishes sleep disorders
linked to a depressed mood (Serfaty et al., 2010).

\textbf{8.9. Oncology}

\textbf{8.9.1. Breast cancer:} Due to its antiestrogenic effects, which
lessen unwanted side effects, melatonin adjuvant therapy is used for
patients who are at risk of developing ER-positive breast cancer
(González-González et al., 2018).

\textbf{8.9.2. Ovarian cancer:} During chemotherapy, melatonin provides
protection to ovaries and fertility preservation (N. Wang et al., 2020).

\textbf{8.9.3. Lung cancer:} Melatonin lessens harm to the ileum, colon,
liver, and lungs. It lessens radiation-induced lung injury and modulates
the effectiveness of DNA repair in humans as well as the genotoxic
activity of irinotecan (Tahamtan et al., 2015).

\textbf{8.9.4. Colorectal cancer:} Because ursolic acid has
antiproliferative and pro-apoptotic effects on colon cancer cells,
melatonin is used to treat this disease (J. Wang et al., 2013).

\textbf{8.10. Viral syndromes}

\textbf{8.10.1. Respiratory Syncytial Virus:} The acute lung oxidative
injury brought on by respiratory syncytial virus is lessened by
melatonin (Huang et al., 2010).

\textbf{8.10.2. Viral myocarditis:} Melatonin is used for the
preservation of cardiac functions and for repression of virus-induced
cardiomyocyte apoptosis. It inhibits apoptosis, regulates the rate of
autophagy, and maintains mitochondrial dysfunction (Ouyang et al.,
2019).

\textbf{8.10.3. Venezuelan equine encephalitis:} Melatonin intake
increases survival rate by reducing virus load in the brain and serum
(Montiel et al., 2015).

\textbf{8.10.4. Encephalomyelitis virus:} Melatonin is used to treat
encephalomyelitis by preventing death and paralysis (Boga et al., 2012).

\textbf{8.10.5. Semliki forest virus:} Melatonin lowers viremia and
postpones disease and death (Ben-Nathan et al., 1995).

\textbf{8.10.6 COVID-19:} Consuming melatonin prolongs survival time by
reducing oxidative damage and slowing down the release of cytokines
(Cross et al., 2021).

\textbf{Future Prospects:}

Future directions in studying the signaling pathways and receptors for
the melatonin hormone appear promising. To better comprehend the
signaling pathways underlying melatonin action, the structure of the MT1
and MT2 receptors in association with various ligands and signaling
molecules must be determined. Recent research has focused on the
implicit role of the MT1 and MT2 receptors in a variety of sleep,
cancer, and metabolic disorders. Creating new medications and adjusting
melatonin's signaling pathways to treat complaints. Just two examples of
the signaling pathways that interact with melatonin signaling are the
cAMP and mitogen-activated protein kinase (MAPK) pathways. To find new
signaling pathways, researchers are examining how the melatonin hormone
binds to receptors that are similar to orphan GPCRs. More study is
required to determine new therapeutic targets for melatonin and its
analogs. More research is required to fully comprehend its mechanisms of
action and to maximize its therapeutic application. Down streaming
signaling mechanism is still unknown. All studies about melatonin
effects were assessed in in-vivo and in-vitro testing and preclinical
trial but lacked significant clinical trials. So there's a huge need to
conduct clinical trials to fully understand long-term melatonin's
physiological effects. The signaling mechanism of melatonin receptors,
their structures and their interaction with the melatonin hormone are
still unknown, so there are a lot of unexplored future directions for
researchers. Researchers may be able to develop potent new treatments
for a variety of diseases and disorders if they learn more about the
receptors involved and the signals they send. Melatonin's regulatory
effects on several physiological systems make it promising for a variety
of therapeutic purposes.

\textbf{Conclusion:}

Melatonin, a hormone produced by the pineal gland, controls circadian
rhythms, sleep-wake cycles, and other physiological processes.
G-protein-coupled receptors (GPCRs), of which two are known as MT1 and
MT2, mediate melatonin's effects on the body. Molecular modeling and
X-ray crystallography are two methods that have been used to determine
the structures of the melatonin type 1 and type 2 receptors. Each of
these receptors has seven transmembrane domains that connect the
intracellular and extracellular domains together. A conformational
change that occurs when melatonin binds to its receptors causes
downstream signaling pathways to become active. Recent research
continues to focus on the receptors and signaling pathways that
melatonin mediates. Due to the multifactorial pathophysiology of
melatonin, the majority of the studies were preclinical, in vitro, with
small sample sizes, and concentrated on short-term results.
Additionally, more research is required because inadequate study methods
constrain decision-making regarding this new use for this medication.
Before applying this knowledge to clinical practice, more clinical
trials with larger sample sizes, precise dosages, and longer durations
are required to confirm the long-term side effects of melatonin. The
investigation of the receptors and signaling mechanisms that melatonin
uses to exert its beneficial therapeutic effects.

\emph{Reference:}

Al-Ghoul, W. M., Herman, M. D., \& Dubocovich, M. L. (1998). Melatonin
receptor subtype expression in human cerebellum: \emph{NeuroReport}
,\emph{9} (18), 4063--4068.
https://doi.org/10.1097/00001756-199812210-00011

Amatruda, T. T., Steele, D. A., Slepak, V. Z., \& Simon, M. I. (1991). G
alpha 16, a G protein alpha subunit specifically expressed in
hematopoietic cells. \emph{Proceedings of the National Academy of
Sciences} , \emph{88} (13), 5587--5591.
https://doi.org/10.1073/pnas.88.13.5587

Bähr, I., Mühlbauer, E., Albrecht, E., \& Peschke, E. (2012). Evidence
of the receptor-mediated influence of melatonin on pancreatic glucagon
secretion via the G\selectlanguage{greek}α\selectlanguage{english}q protein-coupled and PI3K signaling
pathways:\emph{Melatonin receptor and glucagon secretion} .
\emph{Journal of Pineal Research} , \emph{53} (4), 390--398.
https://doi.org/10.1111/j.1600-079X.2012.01009.x

Bahrami, M., Cheraghpour, M., Jafarirad, S., Alavinejad, P., Asadi, F.,
Hekmatdoost, A., Mohammadi, M., \& Yari, Z. (2020). The effect of
melatonin on treatment of patients with non-alcoholic fatty liver
disease: A randomized double blind clinical trial. \emph{Complementary
Therapies in Medicine} , \emph{52} , 102452.
https://doi.org/10.1016/j.ctim.2020.102452

Baker, J., \& Kimpinski, K. (2018). Role of melatonin in blood pressure
regulation: An adjunct anti-hypertensive agent. \emph{Clinical and
Experimental Pharmacology and Physiology} , \emph{45} (8), 755--766.
https://doi.org/10.1111/1440-1681.12942

Ben-Nathan, D., Maestroni, G. J. M., Lustig, S., \& Conti, A. (1995).
Protective effects of melatonin in mice infected with encephalitis
viruses. \emph{Archives of Virology} , \emph{140} (2), 223--230.
https://doi.org/10.1007/BF01309858

Blodgett, D. M., Nowosielska, A., Afik, S., Pechhold, S., Cura, A. J.,
Kennedy, N. J., Kim, S., Kucukural, A., Davis, R. J., Kent, S. C.,
Greiner, D. L., Garber, M. G., Harlan, D. M., \& diIorio, P. (2015).
Novel Observations From Next-Generation RNA Sequencing of Highly
Purified Human Adult and Fetal Islet Cell Subsets. \emph{Diabetes}
,\emph{64} (9), 3172--3181. https://doi.org/10.2337/db15-0039

Boga, J. A., Coto-Montes, A., Rosales-Corral, S. A., Tan, D.-X., \&
Reiter, R. J. (2012). Beneficial actions of melatonin in the management
of viral infections: A new use for this ``molecular handyman''?:
Melatonin and viral infections. \emph{Reviews in Medical Virology}
,\emph{22} (5), 323--338. https://doi.org/10.1002/rmv.1714

Borghi, C., \& Cicero, A. F. G. (2017). Nutraceuticals with a clinically
detectable blood pressure-lowering effect: A review of available
randomized clinical trials and their meta-analyses: Antihypertensive
nutraceuticals. \emph{British Journal of Clinical Pharmacology}
,\emph{83} (1), 163--171. https://doi.org/10.1111/bcp.12902

Brydon, L., Petit, L., Delagrange, P., Strosberg, A. D., \& Jockers, R.
(2001). Functional Expression of MT2 (Mel1b) Melatonin Receptors in
Human PAZ6 Adipocytes. \emph{Endocrinology} , \emph{142} (10),
4264--4271. https://doi.org/10.1210/endo.142.10.8423

Brydon, L., Roka, F., Petit, L., De Coppet, P., Tissot, M., Barrett, P.,
Morgan, P. J., Nanoff, C., Strosberg, A. D., \& Jockers, R. (1999). Dual
Signaling of Human Mel1a Melatonin Receptors via Gi2, Gi3, and Gq/11
Proteins. \emph{Molecular Endocrinology} , \emph{13} (12), 2025--2038.
https://doi.org/10.1210/mend.13.12.0390

Buendia, I., G\selectlanguage{ngerman}ómez-Rangel, V., González-Lafuente, L., Parada, E., León,
R., Gameiro, I., Michalska, P., Laudon, M., Egea, J., \& López, M. G.
(2015). Neuroprotective mechanism of the novel melatonin derivative
Neu-P11 in brain ischemia related models. \emph{Neuropharmacology}
,\emph{99} , 187--195. https://doi.org/10.1016/j.neuropharm.2015.07.014

Chan, A. S. L., Lai, F. P. L., Lo, R. K. H., Voyno-Yasenetskaya, T. A.,
Stanbridge, E. J., \& Wong, Y. H. (2002). Melatonin mt1 and MT2
receptors stimulate c-Jun N-terminal kinase via pertussis
toxin-sensitive and -insensitive G proteins. \emph{Cellular Signalling}
,\emph{14} (3), 249--257. https://doi.org/10.1016/S0898-6568(01)00240-6

Chan, K. H., Tse, L. H., Huang, X., \& Wong, Y. H. (2020). Molecular
basis defining the selectivity of substituted isoquinolinones for the
melatonin MT2 receptor. \emph{Biochemical Pharmacology} , \emph{177} ,
114020. https://doi.org/10.1016/j.bcp.2020.114020

Chaste, P., Clement, N., Botros, H. G., Guillaume, J.-L., Konyukh, M.,
Pagan, C., Scheid, I., Nygren, G., Anckarsäter, H., Rastam, M.,
Ståhlberg, O., Gillberg, I. C., Melke, J., Delorme, R., Leblond, C.,
Toro, R., Huguet, G., Fauchereau, F., Durand, C., \ldots{} Bourgeron, T.
(2011). Genetic variations of the melatonin pathway in patients with
attention-deficit and hyperactivity disorders: The melatonin pathway in
ADHD. \emph{Journal of Pineal Research} , \emph{51} (4), 394--399.
https://doi.org/10.1111/j.1600-079X.2011.00902.x

Chojnacki, C., Walecka-Kapica, E., Lokie\selectlanguage{polish}ć, \selectlanguage{english}K., Paw\selectlanguage{polish}ł\selectlanguage{english}owicz, M., Winczyk,
K., Chojnacki, J., \& Klupi\selectlanguage{polish}ń\selectlanguage{english}ska, G. (2013). Influence of melatonin on
symptoms of irritable bowel syndrome in postmenopausal
women.\emph{Endokrynologia Polska} , \emph{64} (2), 114--120.

Cross, K. M., Landis, D. M., Sehgal, L., \& Payne, J. D. (2021).
Melatonin for the Early Treatment of COVID-19: A Narrative Review of
Current Evidence and Possible Efficacy. \emph{Endocrine Practice}
,\emph{27} (8), 850--855. https://doi.org/10.1016/j.eprac.2021.06.001

Dai, W., Huang, H., Si, L., Hu, S., Zhou, L., Xu, L., \& Deng, Y.
(2019). Melatonin prevents sepsis-induced renal injury via the
PINK1/Parkin1 signaling pathway. \emph{International Journal of
Molecular Medicine} . https://doi.org/10.3892/ijmm.2019.4306

Danilov, A. B., Danilov, A. B., Kurushina, O. V., Shestel, E. A.,
Zhivolupov, S. A., \& Latysheva, N. V. (2020). Safety and Efficacy of
Melatonin in Chronic Tension-Type Headache: A Post-Marketing Real-World
Surveillance Program. \emph{Pain and Therapy} , \emph{9} (2), 741--750.
https://doi.org/10.1007/s40122-020-00207-y

Danilov, A., \& Kurganova, J. (2016). Melatonin in Chronic Pain
Syndromes. \emph{Pain and Therapy} , \emph{5} (1), 1--17.
https://doi.org/10.1007/s40122-016-0049-y

Dinet, V., Ansari, N., Torres-Farfan, C., \& Korf, H.-W. (2007). Clock
gene expression in the retina of melatonin-proficient (C3H) and
melatonin-deficient (C57BL) mice. \emph{Journal of Pineal Research}
,\emph{42} (1), 83--91. https://doi.org/10.1111/j.1600-079X.2006.00387.x

Ding, K., Wang, H., Xu, J., Li, T., Zhang, L., Ding, Y., Zhu, L., He,
J., \& Zhou, M. (2014). Melatonin stimulates antioxidant enzymes and
reduces oxidative stress in experimental traumatic brain injury: The
Nrf2--ARE signaling pathway as a potential mechanism. \emph{Free Radical
Biology and Medicine} , \emph{73} , 1--11.
https://doi.org/10.1016/j.freeradbiomed.2014.04.031

Drew, J., Williams, L., Hannah, L., Barrett, P., \& Abramovich, D.
(1998). Melatonin receptors in the human fetal kidney:
2-{[}125I{]}iodomelatonin binding sites correlated with expression of
Mel1a and Mel1b receptor genes. \emph{Journal of Endocrinology}
,\emph{156} (2), 261--267. https://doi.org/10.1677/joe.0.1560261

Duan, W., Yang, Y., Yi, W., Yan, J., Liang, Z., Wang, N., Li, Y., Chen,
W., Yu, S., Jin, Z., \& Yi, D. (2013). New Role of JAK2/STAT3 Signaling
in Endothelial Cell Oxidative Stress Injury and Protective Effect of
Melatonin. \emph{PLoS ONE} , \emph{8} (3), e57941.
https://doi.org/10.1371/journal.pone.0057941

Dubocovich, M. L. (2003). Molecular pharmacology regulation and function
of mammalian melatonin receptors. \emph{Frontiers in Bioscience}
,\emph{8} (4), d1093-1108. https://doi.org/10.2741/1089

Dubocovich, M. L., Delagrange, P., Krause, D. N., Sugden, D., Cardinali,
D. P., \& Olcese, J. (2010). International Union of Basic and Clinical
Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G
Protein-Coupled Melatonin Receptors. \emph{Pharmacological Reviews}
,\emph{62} (3), 343--380. https://doi.org/10.1124/pr.110.002832

Ekmekcioglu, C. (2006). Melatonin receptors in humans: Biological role
and clinical relevance. \emph{Biomedicine \& Pharmacotherapy} ,\emph{60}
(3), 97--108. https://doi.org/10.1016/j.biopha.2006.01.002

Fallah, R., Shoroki, F., \& Ferdosian, F. (2015). Safety and Efficacy of
Melatonin in Pediatric Migraine Prophylaxis. \emph{Current Drug Safety}
,\emph{10} (2), 132--135.
https://doi.org/10.2174/1574886309666140605114614

Gbahou, F., Cecon, E., Viault, G., Gerbier, R., Jean-Alphonse, F.,
Karamitri, A., Guillaumet, G., Delagrange, P., Friedlander, R. M.,
Vilardaga, J.-P., Suzenet, F., \& Jockers, R. (2017). Design and
validation of the first cell-impermeant melatonin receptor agonist:
Cell-impermeant melatonin receptor agonist. \emph{British Journal of
Pharmacology} , \emph{174} (14), 2409--2421.
https://doi.org/10.1111/bph.13856

Gianesini, C., Hiragaki, S., Laurent, V., Hicks, D., \& Tosini, G.
(2016). Cone Viability Is Affected by Disruption of Melatonin Receptors
Signaling. \emph{Investigative Opthalmology \& Visual Science}
,\emph{57} (1), 94. https://doi.org/10.1167/iovs.15-18235

Gonz\selectlanguage{ngerman}ález-González, A., Mediavilla, M., \& Sánchez-Barceló, E. (2018).
Melatonin: A Molecule for Reducing Breast Cancer Risk. \emph{Molecules}
,\emph{23} (2), 336. https://doi.org/10.3390/molecules23020336

Grima, N. A., Rajaratnam, S. M. W., Mansfield, D., Sletten, T. L.,
Spitz, G., \& Ponsford, J. L. (2018). Efficacy of melatonin for sleep
disturbance following traumatic brain injury: A randomised controlled
trial. \emph{BMC Medicine} , \emph{16} (1), 8.
https://doi.org/10.1186/s12916-017-0995-1

Guo, P., Pi, H., Xu, S., Zhang, L., Li, Y., Li, M., Cao, Z., Tian, L.,
Xie, J., Li, R., He, M., Lu, Y., Liu, C., Duan, W., Yu, Z., \& Zhou, Z.
(2014). Melatonin Improves Mitochondrial Function by Promoting
MT1/SIRT1/PGC-1 Alpha-Dependent Mitochondrial Biogenesis in
Cadmium-Induced Hepatotoxicity In Vitro. \emph{Toxicological Sciences}
,\emph{142} (1), 182--195. https://doi.org/10.1093/toxsci/kfu164

Gupta, M., Aneja, S., \& Kohli, K. (2004). Add-on melatonin improves
quality of life in epileptic children on valproate monotherapy: A
randomized, double-blind, placebo-controlled trial. \emph{Epilepsy \&
Behavior} , \emph{5} (3), 316--321.
https://doi.org/10.1016/j.yebeh.2004.01.012

Hagan, R. M., \& Oakley, N. R. (1995). Melatonin comes of
age?\emph{Trends in Pharmacological Sciences} , \emph{16} (3), 81--83.
https://doi.org/10.1016/S0165-6147(00)88985-3

Hardeland, R. (2012). Melatonin in aging and disease -multiple
consequences of reduced secretion, options and limits of
treatment.\emph{Aging and Disease} , \emph{3} (2), 194--225.

Hazlerigg, D., \& Loudon, A. (2008). New Insights into Ancient Seasonal
Life Timers. \emph{Current Biology} , \emph{18} (17), R795--R804.
https://doi.org/10.1016/j.cub.2008.07.040

Hill, S. M., Belancio, V. P., Dauchy, R. T., Xiang, S., Brimer, S., Mao,
L., Hauch, A., Lundberg, P. W., Summers, W., Yuan, L., Frasch, T., \&
Blask, D. E. (2015). Melatonin: An inhibitor of breast
cancer.\emph{Endocrine-Related Cancer} , \emph{22} (3), R183--R204.
https://doi.org/10.1530/ERC-15-0030

Hiragaki, S., Baba, K., Coulson, E., Kunst, S., Spessert, R., \& Tosini,
G. (2014). Melatonin Signaling Modulates Clock Genes Expression in the
Mouse Retina. \emph{PLoS ONE} , \emph{9} (9), e106819.
https://doi.org/10.1371/journal.pone.0106819

Hirsch-Rodriguez, E., Imbesi, M., Manev, R., Uz, T., \& Manev, H.
(2007). The pattern of melatonin receptor expression in the brain may
influence antidepressant treatment. \emph{Medical Hypotheses} ,\emph{69}
(1), 120--124. https://doi.org/10.1016/j.mehy.2006.11.012

Hotta, C. T., Gazarini, M. L., Beraldo, F. H., Varotti, F. P., Lopes,
C., Markus, R. P., Pozzan, T., \& Garcia, C. R. S. (2000).
Calcium-dependent modulation by melatonin of the circadian rhythm in
malarial parasites. \emph{Nature Cell Biology} , \emph{2} (7), 466--468.
https://doi.org/10.1038/35017112

Hu, K.-L., Ye, X., Wang, S., \& Zhang, D. (2020). Melatonin Application
in Assisted Reproductive Technology: A Systematic Review and
Meta-Analysis of Randomized Trials. \emph{Frontiers in Endocrinology}
,\emph{11} , 160. https://doi.org/10.3389/fendo.2020.00160

Huang, S.-H., Cao, X.-J., Liu, W., Shi, X.-Y., \& Wei, W. (2010).
Inhibitory effect of melatonin on lung oxidative stress induced by
respiratory syncytial virus infection in mice. \emph{Journal of Pineal
Research} , \emph{48} (2), 109--116.
https://doi.org/10.1111/j.1600-079X.2009.00733.x

Imbesi, M., Arslan, A. D., Yildiz, S., Sharma, R., Gavin, D., Tun, N.,
Manev, H., \& Uz, T. (2009). The melatonin receptor MT1 is required for
the differential regulatory actions of melatonin on neuronal `clock'
gene expression in striatal neurons in vitro. \emph{Journal of Pineal
Research} , \emph{46} (1), 87--94.
https://doi.org/10.1111/j.1600-079X.2008.00634.x

Johansson, L. C., Stauch, B., McCorvy, J. D., Han, G. W., Patel, N.,
Huang, X.-P., Batyuk, A., Gati, C., Slocum, S. T., Li, C., Grandner, J.
M., Hao, S., Olsen, R. H. J., Tribo, A. R., Zaare, S., Zhu, L.,
Zatsepin, N. A., Weierstall, U., Yous, S., \ldots{} Cherezov, V. (2019).
XFEL structures of the human MT2 melatonin receptor reveal the basis of
subtype selectivity. \emph{Nature} , \emph{569} (7755), 289--292.
https://doi.org/10.1038/s41586-019-1144-0

Kandil, T. S., Mousa, A. A., El-Gendy, A. A., \& Abbas, A. M. (2010).
The potential therapeutic effect of melatonin in gastro-esophageal
reflux disease. \emph{BMC Gastroenterology} , \emph{10} (1), 7.
https://doi.org/10.1186/1471-230X-10-7

Kato, K., Hirai, K., Nishiyama, K., Uchikawa, O., Fukatsu, K., Ohkawa,
S., Kawamata, Y., Hinuma, S., \& Miyamoto, M. (2005). Neurochemical
properties of ramelteon (TAK-375), a selective MT1/MT2 receptor
agonist.\emph{Neuropharmacology} , \emph{48} (2), 301--310.
https://doi.org/10.1016/j.neuropharm.2004.09.007

Kim, J. W., Jo, J., Kim, J.-Y., Choe, M., Leem, J., \& Park, J.-H.
(2019). Melatonin Attenuates Cisplatin-Induced Acute Kidney Injury
through Dual Suppression of Apoptosis and Necroptosis. \emph{Biology}
,\emph{8} (3), 64. https://doi.org/10.3390/biology8030064

Koziróg, M., Poliwczak, A. R., Duchnowicz, P., Koter-Michalak, M.,
Sikora, J., \& Broncel, M. (2011). Melatonin treatment improves blood
pressure, lipid profile, and parameters of oxidative stress in patients
with metabolic syndrome: Melatonin in metabolic syndrome. \emph{Journal
of Pineal Research} , \emph{50} (3), 261--266.
https://doi.org/10.1111/j.1600-079X.2010.00835.x

Kräuchi, K., Cajochen, C., Werth, E., \& Wirz-Justice, A. (2000).
Functional link between distal vasodilation and sleep-onset
latency?\emph{American Journal of Physiology-Regulatory, Integrative and
Comparative Physiology} , \emph{278} (3), R741--R748.
https://doi.org/10.1152/ajpregu.2000.278.3.R741

Kunst, S., Wolloscheck, T., Kelleher, D. K., Wolfrum, U., Sargsyan, S.
A., Iuvone, P. M., Baba, K., Tosini, G., \& Spessert, R.
(2015).\selectlanguage{greek}\emph{Pgc-1α} \selectlanguage{english}and \emph{Nr4a1} Are Target Genes of Circadian
Melatonin and Dopamine Release in Murine Retina. \emph{Investigative
Opthalmology \& Visual Science} , \emph{56} (10), 6084.
https://doi.org/10.1167/iovs.15-17503

Lanoix, D., Ouellette, R., \& Vaillancourt, C. (2006). Expression of
melatoninergic receptors in human placental choriocarcinoma cell
lines.\emph{Human Reproduction} , \emph{21} (8), 1981--1989.
https://doi.org/10.1093/humrep/del120

Lee, S.-J., Jung, Y. H., Oh, S. Y., Yun, S. P., \& Han, H. J. (2014).
Melatonin enhances the human mesenchymal stem cells motility via
melatonin receptor 2 coupling with G\selectlanguage{greek}α\selectlanguage{english}q in skin wound
healing.\emph{Journal of Pineal Research} , \emph{57} (4), 393--407.
https://doi.org/10.1111/jpi.12179

Lerner, A. B., Case, J. D., Takahashi, Y., Lee, T. H., \& Mori, W.
(1958). ISOLATION OF MELATONIN, THE PINEAL GLAND FACTOR THAT LIGHTENS
MELANOCYTES \textsuperscript{1}. \emph{Journal of the American Chemical
Society} , \emph{80} (10), 2587--2587.
https://doi.org/10.1021/ja01543a060

Li, D., Smith, D., Hardeland, R., Yang, M., Xu, H., Zhang, L., Yin, H.,
\& Zhu, Q. (2013). Melatonin Receptor Genes in
Vertebrates.\emph{International Journal of Molecular Sciences} ,
\emph{14} (6), 11208--11223. https://doi.org/10.3390/ijms140611208

Lin, L., Huang, Q.-X., Yang, S.-S., Chu, J., Wang, J.-Z., \& Tian, Q.
(2013). Melatonin in Alzheimer's Disease. \emph{International Journal of
Molecular Sciences} , \emph{14} (7), 14575--14593.
https://doi.org/10.3390/ijms140714575

Liu, Z., Ran, Y., Qie, S., Gong, W., Gao, F., Ding, Z., \& Xi, J.
(2019). Melatonin protects against ischemic stroke by modulating
microglia/macrophage polarization toward anti-inflammatory phenotype
through STAT3 pathway. \emph{CNS Neuroscience \& Therapeutics}
,\emph{25} (12), 1353--1362. https://doi.org/10.1111/cns.13261

L\selectlanguage{ngerman}ópez-Canul, M., Comai, S., Domínguez-López, S., Granados-Soto, V., \&
Gobbi, G. (2015). Antinociceptive properties of selective MT2 melatonin
receptor partial agonists. \emph{European Journal of Pharmacology}
,\emph{764} , 424--432. https://doi.org/10.1016/j.ejphar.2015.07.010

Lynch, H. J., Wurtman, R. J., Moskowitz, M. A., Archer, M. C., \& Ho, M.
H. (1975). Daily Rhythm in Human Urinary Melatonin. \emph{Science}
,\emph{187} (4172), 169--171. https://doi.org/10.1126/science.1167425

MacKenzie, R. S., Melan, M. A., Passey, D. K., \& Witt-Enderby, P. A.
(2002). Dual coupling of MT1 and MT2 melatonin receptors to cyclic AMP
and phosphoinositide signal transduction cascades and their regulation
following melatonin exposure. \emph{Biochemical Pharmacology} ,\emph{63}
(4), 587--595. https://doi.org/10.1016/S0006-2952(01)00881-4

Maras, A., Schroder, C. M., Malow, B. A., Findling, R. L., Breddy, J.,
Nir, T., Shahmoon, S., Zisapel, N., \& Gringras, P. (2018). Long-Term
Efficacy and Safety of Pediatric Prolonged-Release Melatonin for
Insomnia in Children with Autism Spectrum Disorder. \emph{Journal of
Child and Adolescent Psychopharmacology} , \emph{28} (10), 699--710.
https://doi.org/10.1089/cap.2018.0020

Masana, M. I., Doolen, S., Ersahin, C., Al-Ghoul, W. M., Duckles, S. P.,
Dubocovich, M. L., \& Krause, D. N. (2002). MT
\textsubscript{2}Melatonin Receptors Are Present and Functional in Rat
Caudal Artery.\emph{Journal of Pharmacology and Experimental
Therapeutics} ,\emph{302} (3), 1295--1302.
https://doi.org/10.1124/jpet.302.3.1295

Mathes, A. M. (2010). Hepatoprotective actions of melatonin: Possible
mediation by melatonin receptors. \emph{World Journal of
Gastroenterology} , \emph{16} (48), 6087.
https://doi.org/10.3748/wjg.v16.i48.6087

Mayo, J. C., Sainz, R. M., González Menéndez, P., Cepas, V., Tan, D.-X.,
\& Reiter, R. J. (2017). Melatonin and sirtuins: A ``not-so unexpected''
relationship. \emph{Journal of Pineal Research} , \emph{62} (2), e12391.
https://doi.org/10.1111/jpi.12391

Mazna, P., Grycova, L., Balik, A., Zemkova, H., Friedlova, E., Obsilova,
V., Obsil, T., \& Teisinger, J. (2008). The role of proline residues in
the structure and function of human MT2 melatonin receptor.\emph{Journal
of Pineal Research} , \emph{45} (4), 361--372.
https://doi.org/10.1111/j.1600-079X.2008.00598.x

Mazzucchelli, C., Pannacci, M., Nonno, R., Lucini, V., Fraschini, F., \&
Michaylov Stankov, B. (1996). The melatonin receptor in the human brain:
Cloning experiments and distribution studies. \emph{Molecular Brain
Research} , \emph{39} (1--2), 117--126.
https://doi.org/10.1016/0169-328X(96)00017-4

McArthur, A. J., Hunt, A. E., \& Gillette, M. U. (1997). Melatonin
Action and Signal Transduction in the Rat Suprachiasmatic Circadian
Clock: Activation of Protein Kinase C at Dusk and
Dawn*.\emph{Endocrinology} , \emph{138} (2), 627--634.
https://doi.org/10.1210/endo.138.2.4925

Medeiros, C. A. M., Carvalhedo De Bruin, P. F., Lopes, L. A., Magalhães,
M. C., De Lourdes Seabra, M., \& Sales De Bruin, V. M. (2007). Effect of
exogenous melatonin on sleep and motor dysfunction in Parkinson's
disease: A randomized, double blind, placebo-controlled
study.\emph{Journal of Neurology} , \emph{254} (4), 459--464.
https://doi.org/10.1007/s00415-006-0390-x

Montiel, M., Bonilla, E., Valero, N., Mosquera, J., Espina, L. M.,
Quiroz, Y., \& Álvarez-Mon, M. (2015). Melatonin decreases brain
apoptosis, oxidative stress, and CD200 expression and increased survival
rate in mice infected by Venezuelan equine encephalitis
virus.\emph{Antiviral Chemistry and Chemotherapy} , \emph{24} (3--4),
99--108. https://doi.org/10.1177/2040206616660851

Mühlbauer, E., Gross, E., Labucay, K., Wolgast, S., \& Peschke, E.
(2009). Loss of melatonin signalling and its impact on circadian rhythms
in mouse organs regulating blood glucose. \emph{European Journal of
Pharmacology} , \emph{606} (1--3), 61--71.
https://doi.org/10.1016/j.ejphar.2009.01.029

Nduhirabandi, F., \& Maarman, G. (2018). Melatonin in Heart Failure: A
Promising Therapeutic Strategy? \emph{Molecules} , \emph{23} (7), 1819.
https://doi.org/10.3390/molecules23071819

Nelson, C. S., Marino, J. L., \& Allen, C. N. (1996). Melatonin
receptors activate heteromeric G-protein coupled Kir3
channels:\emph{NeuroReport} , \emph{7} (3), 717--720.
https://doi.org/10.1097/00001756-199602290-00009

Nonno, R., Lucini, V., Spadoni, G., Pannacci, M., Croce, A., Esposti,
D., Balsamini, C., Tarzia, G., Fraschini, F., \& Stankov, B. M. (2000).
A new melatonin receptor ligand with mt1-agonist and MT2-antagonist
properties: A new mt1-agonist and MT2-antagonist melatonin
analog.\emph{Journal of Pineal Research} , \emph{29} (4), 234--240.
https://doi.org/10.1034/j.1600-0633.2002.290406.x

Ouyang, H., Zhong, J., Lu, J., Zhong, Y., Hu, Y., \& Tan, Y. (2019).
Inhibitory effect of melatonin on Mst1 ameliorates myocarditis through
attenuating ER stress and mitochondrial dysfunction. \emph{Journal of
Molecular Histology} , \emph{50} (5), 405--415.
https://doi.org/10.1007/s10735-019-09836-w

Pandiperumal, S., Trakht, I., Srinivasan, V., Spence, D., Maestroni, G.,
Zisapel, N., \& Cardinali, D. (2008). Physiological effects of
melatonin: Role of melatonin receptors and signal transduction
pathways.\emph{Progress in Neurobiology} , \emph{85} (3), 335--353.
https://doi.org/10.1016/j.pneurobio.2008.04.001

Parada, E., Buendia, I., León, R., Negredo, P., Romero, A., Cuadrado,
A., López, M. G., \& Egea, J. (2014). Neuroprotective effect of
melatonin against ischemia is partially mediated by alpha-7 nicotinic
receptor modulation and HO-1 overexpression. \emph{Journal of Pineal
Research} , \emph{56} (2), 204--212. https://doi.org/10.1111/jpi.12113

Petit, L., Lacroix, I., De Coppet, P., Strosberg, A. D., \& Jockers, R.
(1999). Differential signaling of human Mel1a and Mel1b melatonin
receptors through the cyclic guanosine 3\selectlanguage{english}'-5\selectlanguage{english}'-monophosphate
pathway.\emph{Biochemical Pharmacology} , \emph{58} (4), 633--639.
https://doi.org/10.1016/S0006-2952(99)00134-3

Pfeffer, M., Rauch, A., Korf, H.-W., \& Von Gall, C. (2012). The
Endogenous Melatonin (MT) Signal Facilitates Reentrainment of the
Circadian System to Light-Induced Phase Advances by Acting Upon MT2
Receptors. \emph{Chronobiology International} , \emph{29} (4), 415--429.
https://doi.org/10.3109/07420528.2012.667859

Radogna, F., Cristofanon, S., Paternoster, L., D'Alessio, M., De Nicola,
M., Cerella, C., Dicato, M., Diederich, M., \& Ghibelli, L. (2008).
Melatonin antagonizes the intrinsic pathway of apoptosis via
mitochondrial targeting of Bcl-2. \emph{Journal of Pineal Research}
,\emph{44} (3), 316--325.
https://doi.org/10.1111/j.1600-079X.2007.00532.x

Ramirez-Rodriguez, G., Klempin, F., Babu, H., Benitez-King, G., \&
Kempermann, G. (2009). Melatonin Modulates Cell Survival of New Neurons
in the Hippocampus of Adult Mice. \emph{Neuropsychopharmacology}
,\emph{34} (9), 2180--2191. https://doi.org/10.1038/npp.2009.46

Reppert, S. M., Godson, C., Mahle, C. D., Weaver, D. R., Slaugenhaupt,
S. A., \& Gusella, J. F. (1995). Molecular characterization of a second
melatonin receptor expressed in human retina and brain: The Mel1b
melatonin receptor. \emph{Proceedings of the National Academy of
Sciences} , \emph{92} (19), 8734--8738.
https://doi.org/10.1073/pnas.92.19.8734

Reppert, S. M., Weaver, D. R., \& Ebisawa, T. (1994). Cloning and
characterization of a mammalian melatonin receptor that mediates
reproductive and circadian responses. \emph{Neuron} , \emph{13} (5),
1177--1185. https://doi.org/10.1016/0896-6273(94)90055-8

Rossi, S. P., Windschuettl, S., Matzkin, M. E., Terradas, C., Ponzio,
R., Puigdomenech, E., Levalle, O., Calandra, R. S., Mayerhofer, A., \&
Frungieri, M. B. (2014). Melatonin in testes of infertile men: Evidence
for anti-proliferative and anti-oxidant effects on local macrophage and
mast cell populations. \emph{Andrology} , \emph{2} (3), 436--449.
https://doi.org/10.1111/j.2047-2927.2014.00207.x

Rusanova, I., Martinez-Ruiz, L., Florido, J., Rodriguez-Santana, C.,
Guerra-Librero, A., Acuna-Castroviejo, D., \& Escames, G. (2019).
Protective Effects of Melatonin on the Skin: Future
Perspectives.\emph{International Journal of Molecular Sciences} ,
\emph{20} (19), 4948. https://doi.org/10.3390/ijms20194948

Savaskan, E., Jockers, R., Ayoub, M., Angeloni, D., Fraschini, F.,
Flammer, J., Eckert, A., Muller-Spahn, F., \& Meyer, P. (2007). The MT2
Melatonin Receptor Subtype is Present in Human Retina and Decreases in
Alzheimers Disease. \emph{Current Alzheimer Research} , \emph{4} (1),
47--51. https://doi.org/10.2174/156720507779939823

Serfaty, M. A., Osborne, D., Buszewicz, M. J., Blizard, R., \& Raven, P.
W. (2010). A randomized double-blind placebo-controlled trial of
treatment as usual plus exogenous slow-release melatonin (6 mg) or
placebo for sleep disturbance and depressed mood: \emph{International
Clinical Psychopharmacology} , \emph{25} (3), 132--142.
https://doi.org/10.1097/YIC.0b013e32832c260b

Sewerynek, E. (2002). Melatonin and the cardiovascular
system.\emph{Neuro Endocrinology Letters} , \emph{23 Suppl 1} , 79--83.

Sharkey, J. T., Puttaramu, R., Word, R. A., \& Olcese, J. (2009).
Melatonin Synergizes with Oxytocin to Enhance Contractility of Human
Myometrial Smooth Muscle Cells. \emph{The Journal of Clinical
Endocrinology \& Metabolism} , \emph{94} (2), 421--427.
https://doi.org/10.1210/jc.2008-1723

Shu, T., Wu, T., Pang, M., Liu, C., Wang, X., Wang, J., Liu, B., \&
Rong, L. (2016). Effects and mechanisms of melatonin on neural
differentiation of induced pluripotent stem cells. \emph{Biochemical and
Biophysical Research Communications} , \emph{474} (3), 566--571.
https://doi.org/10.1016/j.bbrc.2016.04.108

Soares, J. M., Masana, M. I., Er\selectlanguage{polish}ş\selectlanguage{english}ahin, \selectlanguage{ngerman}Ç., \& Dubocovich, M. L. (2003).
Functional Melatonin Receptors in Rat Ovaries at Various Stages of the
Estrous Cycle. \emph{Journal of Pharmacology and Experimental
Therapeutics} , \emph{306} (2), 694--702.
https://doi.org/10.1124/jpet.103.049916

Stauch, B., Johansson, L. C., McCorvy, J. D., Patel, N., Han, G. W.,
Huang, X.-P., Gati, C., Batyuk, A., Slocum, S. T., Ishchenko, A., Brehm,
W., White, T. A., Michaelian, N., Madsen, C., Zhu, L., Grant, T. D.,
Grandner, J. M., Shiriaeva, A., Olsen, R. H. J., \ldots{} Cherezov, V.
(2019). Structural basis of ligand recognition at the human MT1
melatonin receptor. \emph{Nature} , \emph{569} (7755), 284--288.
https://doi.org/10.1038/s41586-019-1141-3

Steffens, F., Zhou, X.-B., Sausbier, U., Sailer, C., Motejlek, K., Ruth,
P., Olcese, J., Korth, M., \& Wieland, T. (2003). Melatonin Receptor
Signaling in Pregnant and Nonpregnant Rat Uterine Myocytes as Probed by
Large Conductance Ca2+-Activated K+ Channel Activity. \emph{Molecular
Endocrinology} , \emph{17} (10), 2103--2115.
https://doi.org/10.1210/me.2003-0047

Tahamtan, R., Shabestani Monfared, A., Tahamtani, Y., Tavassoli, A.,
Akmali, M., MoslehShirazi, M. A., Naghizadeh, M. M., Ghasemi, D.,
Keshavarz, M., \& Haddadi, G. H. (2015). Radioprotective Effect of
Melatonin on Radiation-Induced Lung Injury and Lipid Peroxidation in
Rats. \emph{Cell Journal (Yakhteh)} , \emph{17} (1).
https://doi.org/10.22074/cellj.2015.517

Tajes, M., Gutierrez-Cuesta, J., Ortuño-Sahagun, D., Camins, A., \&
Pallàs, M. (2009). Anti-aging properties of melatonin in an in vitro
murine senescence model: Involvement of the sirtuin 1
pathway.\emph{Journal of Pineal Research} , \emph{47} (3), 228--237.
https://doi.org/10.1111/j.1600-079X.2009.00706.x

Tan, D.-X., Manchester, L., Esteban-Zubero, E., Zhou, Z., \& Reiter, R.
(2015). Melatonin as a Potent and Inducible Endogenous Antioxidant:
Synthesis and Metabolism. \emph{Molecules} , \emph{20} (10),
18886--18906. https://doi.org/10.3390/molecules201018886

Tan, D.-X., Manchester, L., Qin, L., \& Reiter, R. (2016). Melatonin: A
Mitochondrial Targeting Molecule Involving Mitochondrial Protection and
Dynamics. \emph{International Journal of Molecular Sciences} ,\emph{17}
(12), 2124. https://doi.org/10.3390/ijms17122124

Tavukçu, H. H., \selectlanguage{polish}Ş\selectlanguage{english}ener, T. E., Tinay, \selectlanguage{polish}İ., \selectlanguage{english}Akbal, C., Er\selectlanguage{polish}ş\selectlanguage{english}ahin, M., \selectlanguage{ngerman}Çevik,
Ö., Çad\selectlanguage{polish}ı\selectlanguage{english}rc\selectlanguage{polish}ı, \selectlanguage{english}S., Reiter, R. J., \& \selectlanguage{polish}Ş\selectlanguage{english}ener, G. (2014). Melatonin and
tadalafil treatment improves erectile dysfunction after spinal cord
injury in rats. \emph{Clinical and Experimental Pharmacology and
Physiology} , \emph{41} (4), 309--316.
https://doi.org/10.1111/1440-1681.12216

Uz, T., Arslan, A. D., Kurtuncu, M., Imbesi, M., Akhisaroglu, M.,
Dwivedi, Y., Pandey, G. N., \& Manev, H. (2005). The regional and
cellular expression profile of the melatonin receptor MT1 in the central
dopaminergic system. \emph{Molecular Brain Research} , \emph{136}
(1--2), 45--53. https://doi.org/10.1016/j.molbrainres.2005.01.002

Von Gall, C., Garabette, M. L., Kell, C. A., Frenzel, S., Dehghani, F.,
Schumm-Draeger, P.-M., Weaver, D. R., Korf, H.-W., Hastings, M. H., \&
Stehle, J. H. (2002). Rhythmic gene expression in pituitary depends on
heterologous sensitization by the neurohormone melatonin. \emph{Nature
Neuroscience} , \emph{5} (3), 234--238. https://doi.org/10.1038/nn806

Vriend, J., \& Reiter, R. J. (2015). Melatonin feedback on clock genes:
A theory involving the proteasome. \emph{Journal of Pineal Research}
,\emph{58} (1), 1--11. https://doi.org/10.1111/jpi.12189

Wang, J., Guo, W., Chen, W., Yu, W., Tian, Y., Fu, L., Shi, D., Tong,
B., Xiao, X., Huang, W., \& Deng, W. (2013). Melatonin potentiates the
antiproliferative and pro-apoptotic effects of ursolic acid in colon
cancer cells by modulating multiple signaling pathways. \emph{Journal of
Pineal Research} , \emph{54} (4), 406--416.
https://doi.org/10.1111/jpi.12035

Wang, N., Li, H., Zhu, Y., Li, N., Chen, Z.-J., \& Zhang, C. (2020).
Melatonin protects against Epirubicin-induced ovarian
damage.\emph{Journal of Reproduction and Development} , \emph{66} (1),
19--27. https://doi.org/10.1262/jrd.2019-085

Wang, X., Sirianni, A., Pei, Z., Cormier, K., Smith, K., Jiang, J.,
Zhou, S., Wang, H., Zhao, R., Yano, H., Kim, J. E., Li, W., Kristal, B.
S., Ferrante, R. J., \& Friedlander, R. M. (2011). The Melatonin MT1
Receptor Axis Modulates Mutant Huntingtin-Mediated Toxicity. \emph{The
Journal of Neuroscience} , \emph{31} (41), 14496--14507.
https://doi.org/10.1523/JNEUROSCI.3059-11.2011

West, A., Dupr\selectlanguage{ngerman}é, S. M., Yu, L., Paton, I. R., Miedzinska, K., McNeilly,
A. S., Davis, J. R. E., Burt, D. W., \& Loudon, A. S. I.
(2013).\emph{Npas4} Is Activated by Melatonin, and Drives the Clock
Gene\emph{Cry1} in the Ovine Pars Tuberalis. \emph{Molecular
Endocrinology} ,\emph{27} (6), 979--989.
https://doi.org/10.1210/me.2012-1366

Wu, H., Song, C., Zhang, J., Zhao, J., Fu, B., Mao, T., \& Zhang, Y.
(2017). Melatonin\selectlanguage{english}-mediated upregulation of GLUT1 blocks exit from
pluripotency by increasing the uptake of oxidized vitamin C in mouse
embryonic stem cells. \emph{The FASEB Journal} , \emph{31} (4),
1731--1743. https://doi.org/10.1096/fj.201601085R

Wu, Y.-H., Ursinus, J., Zhou, J.-N., Scheer, F. A. J. L., Ai-Min, B.,
Jockers, R., Van Heerikhuize, J., \& Swaab, D. F. (2013). Alterations of
melatonin receptors MT1 and MT2 in the hypothalamic suprachiasmatic
nucleus during depression. \emph{Journal of Affective Disorders}
,\emph{148} (2--3), 357--367. https://doi.org/10.1016/j.jad.2012.12.025

Zhang, Y., Li, H., Pu, Y., Gong, S., Liu, C., Jiang, X., \& Tao, J.
(2015). Melatonin-mediated inhibition of Purkinje neuron P-type
Ca\textsuperscript{2+} channels in vitro induces neuronal
hyperexcitability through the phosphatidylinositol 3-kinase-dependent
protein kinase C delta pathway. \emph{Journal of Pineal Research}
,\emph{58} (3), 321--334. https://doi.org/10.1111/jpi.12218

Zlotos, Darius. P., Jockers, R., Cecon, E., Rivara, S., \& Witt-Enderby,
P. A. (2014). MT \textsubscript{1} and MT \textsubscript{2} Melatonin
Receptors: Ligands, Models, Oligomers, and Therapeutic
Potential.\emph{Journal of Medicinal Chemistry} , \emph{57} (8),
3161--3185. https://doi.org/10.1021/jm401343c

\textbf{Graphical Abstract:}

\textbf{Figure 1:} Synthetic and Metabolic Pathway of Melatonin

\textbf{Figure 2:} Synthesis of Melatonin through the neurologic pathway
from the pineal gland and its effects.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

\textbf{Figure 3: MT1-Gi and MT2-Gi complex structures:} The complexes
are shown by Cryo-EM density maps. blue colour represents melatonin type
1 receptors; green colour represents melatonin type 2, green; purple
represent G\selectlanguage{greek}α\selectlanguage{english}i in MT1; yellow represent G\selectlanguage{greek}α\selectlanguage{english}i in melatonin type 2; scFV16,
violet is colour code. G\selectlanguage{greek}β, \selectlanguage{english}teal; G\selectlanguage{greek}γ, \selectlanguage{english}light green (b) showed the cryo-EM
structure of MT1-Gi and MT2-Gi. The left side showed
2-iodomelatonin-bound MT1-Gi; the middle side showed ramelteon-bound
MT1-Gi; the right side showed ramelteon-bound MT2-Gi. The right side
shows the structure of ligands and melatonin molecules\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

\textbf{Figure 4: Ligand-binding pocket and selectivity of
determinants.} MT1 has a ligand-binding pocket (yellow) where
2-iodomelatonin (yellow) is bound (blue). B Active (left) and inactive
(right) forms of the ligand access channel MT1 are shown in the slab
view (right, light blue, PDB ID: 6ME4). Ramelteon (pink) is attached to
the ligand-binding pocket in MT2 (green). Schematic slab views of the
active (left) and inactive (right) forms of the MT2 ligand access
channel (right, light cyan, PDB ID: 6ME9). Ligand-binding residues of
MT1 are shown in blue, while those of inactive ligand-binding pockets
are shown in a lighter shade of blue. Red arrows indicate alterations of
note. N162 and Y187 form a 3-f orbital distance hydrogen bond. The
ligand-binding pockets of active (green) and inactive (light cyan) MT2
are contrasted. Red arrows indicate changes of significance. Active MT1
has g 5-HEAT docked in it (cyan). Key residues that are causing problems
in this pocket are shown as sticks. In the open MT1, salmon CTL
01-05-B-A05 has successfully spawned. The red circle denotes the
hydrophobic packing of the naphthalene group and F1945.45. MT2 was open
when salmon CTL 01-05-B-A05 swam in. The Naphthalene group and I2075.45
are packed incompatible, as indicated by the red circle. j Comparison of
the sub pockets from MT1 and MT2 that are active and bound to ramelteon
(red in MT1, yellow in MT2). Sticks represent important distinct
residues.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image6/image6}

\end{center}
\end{figure}

\textbf{Figure 5: Activation of MT1 and MT2 Receptors;} a. The active
structure of the MT1 receptor (blue) and an inactive type 1 receptor
(light blue) are shown and contrasted. There are three perspectives
available. In this image, the TM6 conformation of the Gs-coupled beta2
receptor (right) and the Gi-coupled -opioid receptor (left) is compared
to that of the MT1 molecule. Structures of active (green) and inactive
(light green) MT2 are shown side by side. We see three different
perspectives here. These images show the differences between MT1's TM1
(left) and MT2's ICL2 (right). E--g There are conformational changes in
MT1 motifs and other critical residues during receptor activation.
Structures of active and inactive melatonin receptors 1 and 2 revealed
F6.41 conformations. Gi signaling pathways were visible in I F6.41 from
both MT1 and MT2 mutants. The findings are presented as the means
standard deviations of three separate experiments in which wild-type
receptors were used as a reference.

\textbf{Figure 6 Signalling Pathway:} Melatonin activates MT1 receptors
and activates G\selectlanguage{greek}α\selectlanguage{english}i decreasing cAMP second messenger and activates
PI3K/Akt, PKC, and ERK pathways dependent on G\selectlanguage{greek}βγ. \selectlanguage{english}Intracellular Ca2+
concentration is increased. PLC is activated by Gq coupling to
melatonin. Potassium and calcium on channels are activated by melatonin
and modulate neuronal action mediated and inhibit Ca2+ entry through G\selectlanguage{greek}βγ
\selectlanguage{english}subunits. MT2 receptors are activated by the ERK signaling pathway \&
G\selectlanguage{greek}α\selectlanguage{english}i-dependent cAMP \& inhibited cyclic guanosine monophosphate
synthesis. Recruitment of \selectlanguage{greek}β-\selectlanguage{english}arrestin is induced by melatonin, down
streaming signaling mechanism is still unknown.

\textbf{Figure 7 Signalling pathways:} Different signaling pathways are
activated by melatonin depending on the presence of cell stressors or
cell types. MT1 receptors are mainly involved in these signaling
pathways, and MT2 receptors also participated in these pathways and were
studied in neurodegenerative disorders and under oxidative stress
conditions, involving melatonin modulation of mitochondrial signaling
mechanisms, i.e., translocation of SIRT proteins and Bcl2/Bax is
regulated. The Akt/FOXO1, ERK, and JAK2 complexes activated by melatonin
induce the survival of cells and regulate stem cell differentiation.
These signaling pathways are inhibited by melatonin in cancer cells.
Anti-inflammatory and anti-oxidative effects are regulated by the
transcription factor, i.e., Nrf2, PGC1\selectlanguage{greek}α, \selectlanguage{english}and NF-\selectlanguage{greek}κ\selectlanguage{english}B, which depends on the
activation of SIRT1. In hematopoietic cells, the JNK pathway is
triggered by the coupling of MT1 to G16 protein. Expression of different
miRNAs is regulated by melatonin in different types of cells, i.e.,
cancer cells.

\textbf{Figure 8:} Physiological action of Melatonin hormone

\textbf{Table\#1: MT1 and MT2 Receptor's distribution in Human}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\textbf{Receptor Type} & & \textbf{Tissues} & \textbf{Tissues} &
\textbf{Reference}\tabularnewline
hMT1 & Brain & Cerebellum Occipital cortex Parietal cortex Temporal
cortex Thalamus Frontal cortex Hippocampus & (Mazzucchelli et al., 1996)
(Al-Ghoul et al., 1998) (Mazzucchelli et al., 1996) (Mazzucchelli et
al., 1996) (Mazzucchelli et al., 1996) (Mazzucchelli et al., 1996)
(Mazzucchelli et al., 1996) & (Mazzucchelli et al., 1996) (Al-Ghoul et
al., 1998) (Mazzucchelli et al., 1996) (Mazzucchelli et al., 1996)
(Mazzucchelli et al., 1996) (Mazzucchelli et al., 1996) (Mazzucchelli et
al., 1996)\tabularnewline
& Peripheral tissues & SCN Retina Brown and white adipose tissue Fetal
kidney Coronary artery Granuloma cells Myometrium Pancreatic alpha and
beta cells Testis & (Savaskan et al., 2007) (Reppert et al., 1995)
(Brydon et al., 2001) (Drew et al., 1998) (Soares et al., 2003) (Lanoix
et al., 2006) (Sharkey et al., 2009) (Blodgett et al., 2015) (Rossi et
al., 2014) & (Savaskan et al., 2007) (Reppert et al., 1995) (Brydon et
al., 2001) (Drew et al., 1998) (Soares et al., 2003) (Lanoix et al.,
2006) (Sharkey et al., 2009) (Blodgett et al., 2015) (Rossi et al.,
2014)\tabularnewline
hMT2 & Brain & Cerebellum Hippocampus SCN & (Al-Ghoul et al., 1998)
(Savaskan et al., 2007) (Y.-H. Wu et al., 2013) & (Al-Ghoul et al.,
1998) (Savaskan et al., 2007) (Y.-H. Wu et al., 2013)\tabularnewline
& Peripheral tissues & Retina Brown and white adipose tissue Fetal
kidney Granulosa cells Placental tissues Myometrium Pancreatic alpha and
beta cells Testis & (Reppert et al., 1995) (Brydon et al., 2001) (Drew
et al., 1998) (Soares et al., 2003) (Lanoix et al., 2006) (Sharkey et
al., 2009) (Kato et al., 2005) (Rossi et al., 2014) & (Reppert et al.,
1995) (Brydon et al., 2001) (Drew et al., 1998) (Soares et al., 2003)
(Lanoix et al., 2006) (Sharkey et al., 2009) (Kato et al., 2005) (Rossi
et al., 2014)\tabularnewline
\bottomrule
\end{longtable}

\selectlanguage{english}
\FloatBarrier
\end{document}

