Melatonin receptor

Last updated
melatonin receptor 1A
Identifiers
SymbolMTNR1A
NCBI gene 4543
HGNC 7463
OMIM 600665
RefSeq NM_005958
UniProt P48039
Other data
Locus Chr. 4 q35.1
Search for
Structures Swiss-model
Domains InterPro
melatonin receptor 1B
Identifiers
SymbolMTNR1B
NCBI gene 4544
HGNC 7464
OMIM 600804
RefSeq NM_005959
UniProt P49286
Other data
Locus Chr. 11 q21-q22
Search for
Structures Swiss-model
Domains InterPro

Melatonin receptors are G protein-coupled receptors (GPCR) which bind melatonin. [1] Three types of melatonin receptors have been cloned. The MT1 (or Mel1A or MTNR1A) and MT2 (or Mel1B or MTNR1B) receptor subtypes are present in humans and other mammals, [2] while an additional melatonin receptor subtype MT3 (or Mel1C or MTNR1C) has been identified in amphibia and birds. [3] The receptors are crucial in the signal cascade of melatonin. In the field of chronobiology, melatonin has been found to be a key player in the synchrony of biological clocks. Melatonin secretion by the pineal gland has circadian rhythmicity regulated by the suprachiasmatic nucleus (SCN) found in the brain. The SCN functions as the timing regulator for melatonin; melatonin then follows a feedback loop to decrease SCN neuronal firing. The receptors MT1 and MT2 control this process. [4] Melatonin receptors are found throughout the body in places such as the brain, the retina of the eye, the cardiovascular system, the liver and gallbladder, the colon, the skin, the kidneys, and many others. [5] In 2019, X-ray crystal and cryo-EM structures of MT1 and MT2 were reported. [6] [7] [8] [9]

Contents

History

Melatonin has been known about since the beginning of the 20th century with experiments led by Carey P. McCord and Floyd P. Allen. The two scientists obtained extracts of the pineal gland from bovines and noticed its blanching effects on the skin of tadpoles. The melatonin chemical was found and isolated in the pineal gland in 1958 by physician Aaron B. Lerner. Due to its ability to lighten skin, Lerner named the compound melatonin. [10] Discovery of high affinity binding sites for melatonin were found near the end of the 20th century. The experiment to find these binding sites utilized an expression cloning strategy to isolate the site. The receptor was first cloned from the melanophores of Xenopus laevis. In recent years, research with melatonin has shown to improve neurological disorders such as Parkinson's, Alzheimer's disease, brain edema, and traumatic brain injury, alcoholism, and depression. [10] Also, regulation of addictive behavior has been associated with the increase of melatonin receptor-related cAMP in the mesolimbic dopaminergic system. [5] Melatonin treatment has also been studied as a remedy of disturbed circadian rhythms found in conditions such a jet lag, shift work, and types of insomnia. [4]

Function and regulation

General

Melatonin serves a variety of functions throughout the body. While its role in sleep promotion is its most well known, melatonin has its hands in a wide range of biological processes. In addition to sleep promotion, melatonin also regulates hormone secretion, rhythms in reproductive activity, immune functionality, and circadian rhythms. [11] Further, melatonin functions as a neuroprotective, pain-reducer, tumor suppressor, reproduction stimulant, and antioxidant. [5] Melatonin has an anti-excitatory effect on brain activity which is exemplified by its reduction of epileptic activity in children which is to say that it is an inhibitory transmitter. [5] The functional diversity of the melatonin receptors contribute to the range of influence that melatonin has over various biological processes. Some of the functions/effects of melatonin binding to its receptor have been linked to one of the specific versions of the receptor that has been discriminated (MT1, MT2, MT3). The expression patterns in melatonin receptors are unique and brain area specific. [12] In mammals, melatonin receptors are found in the brain and some peripheral organs. However, there is considerable variation in the density and location of MT receptor expression between species, and the receptors show different affinities for different ligands. [13]

MT1

The sleep promoting effects of melatonin has been tied to the activation of the MT1 receptor in the suprachiasmatic nucleus (SCN) which has an inhibitory effect on brain activity. [11] While the phase shifting activity of melatonin has largely been linked to the MT2 receptor, there is evidence to suggest that the MT1 receptor plays a role in the process of entrainment to light-dark cycles. This evidence comes from an experiment in which wild-type (WT) mice and MT1 knock-out (KO) mice were given melatonin and their rates of entrainment were observed. [11] Entrainment was observed to accelerate in WT mice upon melatonin dosage but not in MT1 KO mice which lead to the conclusion that MT1 plays a role in phase-shifting activity.

Expression Patterns
The MT1 melatonin receptor sits on the cell membrane. In humans it consists of 351 amino acids that are encoded in chromosome 4. [5] Its main function here is as an adenylate cyclase inhibitor, which works when MT1 binds to other G-proteins. In humans, The MT1 subtype is expressed in the pars tuberalis of the pituitary gland, the retina, and the suprachiasmatic nuclei of the hypothalamus, and are most likely found in human skin. As humans age, the expression of MT1 and the SCN decreases because MT1 reaction rate decreases and prolactin secretion decreases. [5]

MT2

The MT2 receptor has been shown to serve several functions in the body. In humans, the MT2 subtype's expression in the retina is suggestive of melatonin's effect on the mammalian retina occurring through this receptor. Research suggests that melatonin acts to inhibit the Ca2+-dependent release of dopamine. [14] Melatonin's action in the retina is believed to affect several light-dependent functions, including phagocytosis and photopigment disc shedding. [15] In addition to retina this receptor is expressed on the osteoblasts and is increased upon their differentiation. MT2 regulates proliferation and differentiation of osteoblasts and regulates their function in depositing bone.[ citation needed ] MT2 signaling seems also involved in the pathogenesis of type 2 diabetes. Activation of the MT2 receptor promotes vasodilation which lowers body temperature in the extremities upon daytime administration. [5] The most notable of the functions that are largely mediated by the MT2 receptor is that of phase shifting the internal circadian clock to entrain to the Earth's natural light-dark cycle. As noted above, the MT1 receptor has been shown to have a hand in phase shifting but this role is secondary to that of the MT2 receptor. [11] In experiments involving MT1 KO mice (and WT as a control) both WT and MT1 KO groups exhibited phase shifting activity. On the flip side, MT2 KO mice were not able to phase shift suggesting that the MT2 receptor is necessary for phase shifting the internal circadian clock.

Expression Patterns
The MT2 (cell membrane) subtype is expressed in the retina, and are also found in skin; [5] MT2 receptor mRNA has not been detected by in situ hybridization in the rat suprachiasmatic nucleus or pars tuberalis. [14] The MT2 receptor is found in chromosome four, of humans, and consists of 351 amino acids. [5] Recently, scientists have been studying the relationship between the MT2 receptor and sleep disorders, anxiety, depression, and pain. Since it was found that MT2 receptors contribute to sleep regulation, through NREMS, [16] and has anxiety reducing effects, [17] scientists have begun to consider MT2 as a treatment target for the aforementioned afflictions. [5] [18]

MT3

While MT3 has been briefly described in its potential role of regulating fluid pressure inside the eye, it does not carry the same relevance to critical biological process such as sleep promotion, locomotor activity, and circadian rhythm regulation that MT1 and MT2 do. MT3 also serves a detoxification role in liver, heart, intestine, kidney, muscle and fat.

Expression Patterns
The MT3 subtype of many non-mammalian vertebrates is expressed in various brain areas. [3] MT3 is also known as a reductase detoxification enzyme (quinone reductase 2). [5] The enzyme finds its home largely in the "liver, kidney, heart, lung, intestine, muscle and brown fat tissue".... and there is significant research that supports the claim that MT3 helps regulate the pressure that develops on the inside of the eye. [5]

Melatonin binding

The melatonin receptors MT1 and MT2 are G-protein coupled receptors (GPCRs) that typically adhere to the cell's surface so that they can receive external melatonin signals. Binding of melatonin to the MT1 receptor leads to inhibition of cAMP production and Protein Kinase A (PKA). [5] While activation of the MT2 receptor is also shown to inhibit the production of cAMP, it additionally inhibits cGMP production. [5] Melatonin binding to the MT1 and MT2 receptors is only one of the paths through which it shows its influence. In addition to binding to membrane bound GPCRs (MT1 and MT2) melatonin also binds to intracellular and nuclear receptors.

Regulation of melatonin receptors

The different types of melatonin receptors are regulated in different ways. When the MT1 receptor is exposed to typical levels of melatonin, there is no change in cell membrane receptor density, affinity for substrate, or functional sensitivity. [11] However, the same trend is not shown in MT2 receptors. Administration of typical levels of melatonin resulted in the removal of MT2 receptors from the membrane (internalization) and a decrease in the sensitivity of the receptor to melatonin. [11] These responses help the MT2 receptor accomplish its role in phase shifting the circadian clock by adjusting the sensitivity and availability of the population of MT2 to melatonin. This desensitization and/or internalization is characteristic of many GPCRs. Often, binding of melatonin to MT2 and subsequent desensitization can lead to the internalization of that receptor which decreases the availability of membrane bound melatonin receptor which will prevent additional melatonin from having as robust of an effect as the initial application. [11] Since there are regular rhythms in both of these receptor subtypes, the internalization and resulting decrease in receptor availability following administration of typical levels of melatonin will effectively shift the phase of this rhythm in MT2. The behavior of each of these receptors under prolonged exposure to their chief agonist - melatonin - is indicative of the functions that they are each crucial to.

Role in circadian rhythms

Since the SCN is responsible for mediating the production of melatonin by the pineal gland, it creates a feedback loop that regulates the production of melatonin according to the master circadian clock. [11] As was discussed previously, the MT1 receptor is largely thought of as the major player in sleep-promotion and the MT2 receptor is most strongly linked to phase shifting activity. Both major subtypes of the melatonin receptor are expressed in relatively large amounts in the SCN which allow it to both regulate sleep-wake cycles and induce phase shifting in response to natural light-dark cycles. [11] This functional diversity of melatonin receptors helps give the SCN the ability to not only keep near 24-hour time and entrain to an exactly 24-hour period, but also regulate, among other factors, wakefulness and activity throughout this cycle.

Dysfunction and supplemental melatonin

Melatonin's role as a hormone in the body is its most widely known and the primary target of supplemental melatonin. Many people who struggle with falling asleep utilize melatonin supplements to help induce the onset of their sleep. However, melatonin's influence on the body extends much further than simple sleep promotion. Melatonin has also been described as a "cellular protector". Studies have found that higher circadian levels of melatonin correspond to lower rates of breast cancer while abnormally low serum melatonin levels can increase a woman's chance of developing breast cancer.[ citation needed ] Irregular/arrhythmic melatonin levels has, in addition to cancer, been linked to development of cardiovascular disease. [19]

Selective ligands

Agonists

Antagonists

See also

Related Research Articles

Free-running sleep is a rare sleep pattern whereby the sleep schedule of a person shifts later every day. It occurs as the sleep disorder non-24-hour sleep–wake disorder or artificially as part of experiments used in the study of circadian and other rhythms in biology. Study subjects are shielded from all time cues, often by a constant light protocol, by a constant dark protocol or by the use of light/dark conditions to which the organism cannot entrain such as the ultrashort protocol of one hour dark and two hours light. Also, limited amounts of food may be made available at short intervals so as to avoid entrainment to mealtimes. Subjects are thus forced to live by their internal circadian "clocks".

Jet lag is a physiological condition that results from alterations to the body's circadian rhythms caused by rapid long-distance trans-meridian travel. For example, someone flying from New York to London, i.e. from west to east, feels as if the time were five hours earlier than local time, and someone travelling from London to New York, i.e. from east to west, feels as if the time were five hours later than local time. The phase shift when traveling from east to west is referred to as phase-delay of the circadian circle, whereas going west to east is phase-advance of the circadian circle. Most travelers find that it is harder to timezone adjust when traveling to the east. Jet lag was previously classified as one of the circadian rhythm sleep disorders.

<span class="mw-page-title-main">Circadian rhythm</span> Natural internal process that regulates the sleep-wake cycle

A circadian rhythm, or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism and responds to the environment. These 24-hour rhythms are driven by a circadian clock, and they have been widely observed in animals, plants, fungi and cyanobacteria.

<span class="mw-page-title-main">Chronobiology</span> Field of biology

Chronobiology is a field of biology that examines timing processes, including periodic (cyclic) phenomena in living organisms, such as their adaptation to solar- and lunar-related rhythms. These cycles are known as biological rhythms. Chronobiology comes from the ancient Greek χρόνος, and biology, which pertains to the study, or science, of life. The related terms chronomics and chronome have been used in some cases to describe either the molecular mechanisms involved in chronobiological phenomena or the more quantitative aspects of chronobiology, particularly where comparison of cycles between organisms is required.

<span class="mw-page-title-main">Pineal gland</span> Endocrine gland in the brain of most vertebrates

The pineal gland, conarium, or epiphysis cerebri, is a small endocrine gland in the brain of most vertebrates. The pineal gland produces melatonin, a serotonin-derived hormone which modulates sleep patterns in both circadian and seasonal cycles. The shape of the gland resembles a pine cone, which gives it its name. The pineal gland is located in the epithalamus, near the center of the brain, between the two hemispheres, tucked in a groove where the two halves of the thalamus join. The pineal gland is one of the neuroendocrine secretory circumventricular organs in which capillaries are mostly permeable to solutes in the blood.

<span class="mw-page-title-main">Melatonin</span> Hormone released by the pineal gland

Melatonin is a natural product found in plants and animals. It is primarily known in animals as a hormone released by the pineal gland in the brain at night, and has long been associated with control of the sleep–wake cycle.

<span class="mw-page-title-main">Suprachiasmatic nucleus</span> Part of the brains hypothalamus

The suprachiasmatic nucleus or nuclei (SCN) is a tiny region of the brain in the hypothalamus, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms. The neuronal and hormonal activities it generates regulate many different body functions in a 24-hour cycle. The mouse SCN contains approximately 20,000 neurons.

<span class="mw-page-title-main">Pinealocyte</span> Main cells contained in the pineal gland

Pinealocytes are the main cells contained in the pineal gland, located behind the third ventricle and between the two hemispheres of the brain. The primary function of the pinealocytes is the secretion of the hormone melatonin, important in the regulation of circadian rhythms. In humans, the suprachiasmatic nucleus of the hypothalamus communicates the message of darkness to the pinealocytes, and as a result, controls the day and night cycle. It has been suggested that pinealocytes are derived from photoreceptor cells. Research has also shown the decline in the number of pinealocytes by way of apoptosis as the age of the organism increases. There are two different types of pinealocytes, type I and type II, which have been classified based on certain properties including shape, presence or absence of infolding of the nuclear envelope, and composition of the cytoplasm.

<span class="mw-page-title-main">Melanopsin</span> Mammalian protein found in Homo sapiens

Melanopsin is a type of photopigment belonging to a larger family of light-sensitive retinal proteins called opsins and encoded by the gene Opn4. In the mammalian retina, there are two additional categories of opsins, both involved in the formation of visual images: rhodopsin and photopsin in the rod and cone photoreceptor cells, respectively.

Non-24-hour sleep–wake disorder is one of several chronic circadian rhythm sleep disorders (CRSDs). It is defined as a "chronic steady pattern comprising [...] daily delays in sleep onset and wake times in an individual living in a society". Symptoms result when the non-entrained (free-running) endogenous circadian rhythm drifts out of alignment with the light–dark cycle in nature. Although this sleep disorder is more common in blind people, affecting up to 70% of the totally blind, it can also affect sighted people. Non-24 may also be comorbid with bipolar disorder, depression, and traumatic brain injury. The American Academy of Sleep Medicine (AASM) has provided CRSD guidelines since 2007 with the latest update released in 2015.

Intrinsically photosensitive retinal ganglion cells (ipRGCs), also called photosensitive retinal ganglion cells (pRGC), or melanopsin-containing retinal ganglion cells (mRGCs), are a type of neuron in the retina of the mammalian eye. The presence of ipRGCs was first suspected in 1927 when rodless, coneless mice still responded to a light stimulus through pupil constriction, This implied that rods and cones are not the only light-sensitive neurons in the retina. Yet research on these cells did not advance until the 1980s. Recent research has shown that these retinal ganglion cells, unlike other retinal ganglion cells, are intrinsically photosensitive due to the presence of melanopsin, a light-sensitive protein. Therefore they constitute a third class of photoreceptors, in addition to rod and cone cells.

Circadian rhythm sleep disorders (CRSD), also known as circadian rhythm sleep-wake disorders (CRSWD), are a family of sleep disorders which affect the timing of sleep. CRSDs arise from a persistent pattern of sleep/wake disturbances that can be caused either by dysfunction in one's biological clock system, or by misalignment between one's endogenous oscillator and externally imposed cues. As a result of this mismatch, those affected by circadian rhythm sleep disorders have a tendency to fall asleep at unconventional time points in the day. These occurrences often lead to recurring instances of disturbed rest, where individuals affected by the disorder are unable to go to sleep and awaken at "normal" times for work, school, and other social obligations. Delayed sleep phase disorder, advanced sleep phase disorder, non-24-hour sleep–wake disorder and irregular sleep–wake rhythm disorder represents the four main types of CRSD.

<span class="mw-page-title-main">Retinohypothalamic tract</span> Neural pathway involved with circadian rhythms

In neuroanatomy, the retinohypothalamic tract (RHT) is a photic neural input pathway involved in the circadian rhythms of mammals. The origin of the retinohypothalamic tract is the intrinsically photosensitive retinal ganglion cells (ipRGC), which contain the photopigment melanopsin. The axons of the ipRGCs belonging to the retinohypothalamic tract project directly, monosynaptically, to the suprachiasmatic nuclei (SCN) via the optic nerve and the optic chiasm. The suprachiasmatic nuclei receive and interpret information on environmental light, dark and day length, important in the entrainment of the "body clock". They can coordinate peripheral "clocks" and direct the pineal gland to secrete the hormone melatonin.

<span class="mw-page-title-main">Melatonin receptor 1A</span>

Melatonin receptor type 1A is a protein that in humans is encoded by the MTNR1A gene.

Light effects on circadian rhythm are the effects that light has on circadian rhythm.

<span class="mw-page-title-main">Melatonin receptor 1B</span>

Melatonin receptor 1B, also known as MTNR1B, is a protein that in humans is encoded by the MTNR1B gene.

Steven M. Reppert is an American neuroscientist known for his contributions to the fields of chronobiology and neuroethology. His research has focused primarily on the physiological, cellular, and molecular basis of circadian rhythms in mammals and more recently on the navigational mechanisms of migratory monarch butterflies. He was the Higgins Family Professor of Neuroscience at the University of Massachusetts Medical School from 2001 to 2017, and from 2001 to 2013 was the founding chair of the Department of Neurobiology. Reppert stepped down as chair in 2014. He is currently distinguished professor emeritus of neurobiology.

<span class="mw-page-title-main">Melatonin receptor agonist</span>

Melatonin receptor agonists are analogues of melatonin that bind to and activate the melatonin receptor. Agonists of the melatonin receptor have a number of therapeutic applications including treatment of sleep disorders and depression. The discovery and development of melatonin receptor agonists was motivated by the need for more potent analogues than melatonin, with better pharmacokinetics and longer half-lives. Melatonin receptor agonists were developed with the melatonin structure as a model.

A chronobiotic is an agent that can cause phase adjustment of the circadian rhythm. That is, it is a substance capable of therapeutically entraining or re-entraining long-term desynchronized or short-term dissociated circadian rhythms in mammals, or prophylactically preventing their disruption following an environmental insult such as is caused by rapid travel across several time zones. The most widely recognized chronobiotic is the hormone melatonin, secreted at night in both diurnal and nocturnal species.

Michael Menaker, was an American chronobiology researcher, and was Commonwealth Professor of Biology at University of Virginia. His research focused on circadian rhythmicity of vertebrates, including contributing to an understanding of light input pathways on extra-retinal photoreceptors of non-mammalian vertebrates, discovering a mammalian mutation for circadian rhythmicity, and locating a circadian oscillator in the pineal gland of bird. He wrote almost 200 scientific publications.

References

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