Melatonin receptors are G protein-coupled receptors (GPCR) which bind melatonin. 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, while an additional melatonin receptor subtype MT3 (or Mel1C or MTNR1C) has been identified in amphibia and birds. 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. 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. In 2019, X-ray crystal and cryo-EM structures of MT1 and MT2 were reported.
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. 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. Also, regulation of addictive behavior has been associated with the increase of melatonin receptor-related cAMP in the mesolimbic dopaminergic system. Melatonin treatment has also been studied as a remedy of disturbed circadian rhythms found in conditions such as jet lag, shift work, and types of insomnia.
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. Further, melatonin functions as a neuroprotective, pain-reducer, tumor suppressor, reproduction stimulant, and antioxidant. 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. 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. 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.
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. 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. 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. 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.
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. Melatonin's action in the retina is believed to affect several light-dependent functions, including phagocytosis and photopigment disc shedding. 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. 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. 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. 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.
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