Melatonin receptor

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melatonin receptor 1A
Other data
LocusChr. 4 q35.1
melatonin receptor 1B
Other data
LocusChr. 11 q21-q22

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 the SCN to decrease SCN neuronal firing. The receptors MT1 and MT2 in the SCN control this process.[4] Melatonin receptors are found throughout the body in places such as brain, retina, cardiovascular system, aorta, coronary and cerebral arteries, liver and gallbladder, colon, skin, kidney, and many others.[5]


Melatonin has been known about since the beginning of the 20th century with experiments lead by McCord and 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 Dr.Aaron B. Lerner. Due to its ability to lighten skin, Dr.Lerner named the compound melatonin.[6] Discovery of high affinity binding sites for melatonin were found near the end of the 20th century. 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. 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]

Expression patterns[edit]

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.[7]


In humans, The MT1 subtype is expressed in the pars tuberalis of the pituitary gland, the retina and the suprachiasmatic nuclei of the hypothalamus.


The MT2 subtype is expressed in the retina. MT2 receptor mRNA has not been detected by in situ hybridization in the rat suprachiasmatic nucleus or pars tuberalis.[8]


The MT3 subtype of many non-mammalian vertebrates is expressed in various brain areas.[3]

Function and regulation[edit]


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.[9] 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 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.[9] 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.[9] 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.


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.[8] Melatonin's action in the retina is believed to affect several light-dependent functions, including phagocytosis and photopigment disc shedding.[10] 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. [11] 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.[9] 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.


While MT3 has been briefly described in its potential roll of regulating fluid pressure inside the eye, it is 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 roll in liver, heart, intestine, kidney, muscle and fat.

Melatonin binding[edit]

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 the inhibition of the production of cAMP through inhibition of 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[edit]

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.[9] 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.[9] These responses help the MT2 receptor accomplish its role in phase shifting the circadian clock. 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[edit]

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.[9] 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.[9] 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.

Selective ligands[edit]



See also[edit]


  1. ^ Reppert SM (December 1997). "Melatonin receptors: molecular biology of a new family of G protein-coupled receptors". Journal of Biological Rhythms. 12 (6): 528–31. doi:10.1177/074873049701200606. PMID 9406026.
  2. ^ Reppert SM, Weaver DR, Godson C (March 1996). "Melatonin receptors step into the light: cloning and classification of subtypes". Trends in Pharmacological Sciences. 17 (3): 100–2. doi:10.1016/0165-6147(96)10005-5. PMID 8936344.
  3. ^ a b Sugden D, Davidson K, Hough KA, Teh MT (October 2004). "Melatonin, melatonin receptors and melanophores: a moving story". Pigment Cell Research. 17 (5): 454–60. doi:10.1111/j.1600-0749.2004.00185.x. PMID 15357831.
  4. ^ a b Doghramji K (August 2007). "Melatonin and its receptors: a new class of sleep-promoting agents". Journal of Clinical Sleep Medicine. 3 (5 Suppl): S17–23. PMC 1978320. PMID 17824497.
  5. ^ a b c d e f g Emet M, Ozcan H, Ozel L, Yayla M, Halici Z, Hacimuftuoglu A (June 2016). "A Review of Melatonin, Its Receptors and Drugs". The Eurasian Journal of Medicine. 48 (2): 135–41. doi:10.5152/eurasianjmed.2015.0267. PMC 4970552. PMID 27551178.
  6. ^ Zlotos DP, Jockers R, Cecon E, Rivara S, Witt-Enderby PA (April 2014). "MT1 and MT2 melatonin receptors: ligands, models, oligomers, and therapeutic potential". Journal of Medicinal Chemistry. 57 (8): 3161–85. doi:10.1021/jm401343c. PMID 24228714.
  7. ^ Morgan PJ, Barrett P, Howell HE, Helliwell R (February 1994). "Melatonin receptors: localization, molecular pharmacology and physiological significance". Neurochemistry International. 24 (2): 101–46. doi:10.1016/0197-0186(94)90100-7. PMID 8161940.
  8. ^ a b Reppert SM, Godson C, Mahle CD, Weaver DR, Slaugenhaupt SA, Gusella JF (September 1995). "Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor". Proceedings of the National Academy of Sciences of the United States of America. 92 (19): 8734–8. Bibcode:1995PNAS...92.8734R. doi:10.1073/pnas.92.19.8734. PMC 41041. PMID 7568007.
  9. ^ a b c d e f g h Dubocovich ML (December 2007). "Melatonin receptors: role on sleep and circadian rhythm regulation". Sleep Medicine. 8 Suppl 3: 34–42. doi:10.1016/j.sleep.2007.10.007. PMID 18032103.
  10. ^ Besharse JC, Dunis DA (March 1983). "Methoxyindoles and photoreceptor metabolism: activation of rod shedding". Science. 219 (4590): 1341–3. Bibcode:1983Sci...219.1341B. doi:10.1126/science.6828862. PMID 6828862.
  11. ^ Sharan K, Lewis K, Furukawa T, Yadav VK (September 2017). "Regulation of bone mass through pineal-derived melatonin-MT2 receptor pathway". Journal of Pineal Research. 63 (2). doi:10.1002/jbm.a.30786. PMC 5575491. PMID 28512916.
  12. ^ Nickelsen T, Samel A, Vejvoda M, Wenzel J, Smith B, Gerzer R (September 2002). "Chronobiotic effects of the melatonin agonist LY 156735 following a simulated 9h time shift: results of a placebo-controlled trial". Chronobiology International. 19 (5): 915–36. doi:10.1081/cbi-120014108. PMID 12405554.

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