Melatonin receptor 1B, also known as MTNR1B, is a protein that in humans is encoded by the MTNR1B gene. [5] [6]
Melatonin receptor 1B, also known as MTNR1B, is a protein that in humans is encoded by the MTNR1B gene. [5] [6]
This gene encodes the MT2 protein, one of two high-affinity forms of a receptor for melatonin, the primary hormone secreted by the pineal gland. This gene product is an integral membrane protein that is a G-protein coupled, 7-transmembrane receptor. It is found primarily in the retina and brain; however, this detection requires RT-PCR. It is thought to participate in light-dependent functions in the retina and may be involved in the neurobiological effects of melatonin. [5] Besides the brain and retina this receptor is expressed on the bone forming cells where it regulates their function in depositing bone. [7]
Several studies have identified MTNR1B receptor mutations that are associated with increased average blood sugar level and around a 20 percent elevated risk of developing type 2 diabetes. [8] [9] [10] MTNR1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in beta cells in islets. [9]
The following MT2R ligands have selectivity over MT1R:
The pineal gland 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. It is one of the neuroendocrine secretory circumventricular organs in which capillaries are mostly permeable to solutes in the blood.
Melatonin is a natural compound, specifically an indoleamine, produced by and found in different organisms including bacteria and eukaryotes. It was discovered by Aaron B. Lerner and colleagues in 1958 as a substance of the pineal gland from cow that could induce skin lightening in common frogs. It was subsequently discovered as a hormone released in the brain at night which controls the sleep–wake cycle in vertebrates.
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.
Animal opsins are G-protein-coupled receptors and a group of proteins made light-sensitive via a chromophore, typically retinal. When bound to retinal, opsins become Retinylidene proteins, but are usually still called opsins regardless. Most prominently, they are found in photoreceptor cells of the retina. Five classical groups of opsins are involved in vision, mediating the conversion of a photon of light into an electrochemical signal, the first step in the visual transduction cascade. Another opsin found in the mammalian retina, melanopsin, is involved in circadian rhythms and pupillary reflex but not in vision. Humans have in total nine opsins. Beside vision and light perception, opsins may also sense temperature, sound, or chemicals.
The chemokine ligand 2 (CCL2) is also referred to as monocyte chemoattractant protein 1 (MCP1) and small inducible cytokine A2. CCL2 is a small cytokine that belongs to the CC chemokine family. CCL2 tightly regulates cellular mechanics and thereby recruits monocytes, memory T cells, and dendritic cells to the sites of inflammation produced by either tissue injury or infection.
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.
Aralkylamine N-acetyltransferase (AANAT), also known as arylalkylamine N-acetyltransferase or serotonin N-acetyltransferase (SNAT), is an enzyme that is involved in the day/night rhythmic production of melatonin, by modification of serotonin. It is in humans encoded by the ~2.5 kb AANAT gene containing four exons, located on chromosome 17q25. The gene is translated into a 23 kDa large enzyme. It is well conserved through evolution and the human form of the protein is 80 percent identical to sheep and rat AANAT. It is an acetyl-CoA-dependent enzyme of the GCN5-related family of N-acetyltransferases (GNATs). It may contribute to multifactorial genetic diseases such as altered behavior in sleep/wake cycle and research is on-going with the aim of developing drugs that regulate AANAT function.
N-Acetylserotonin O-methyltransferase, also known as ASMT, is an enzyme which catalyzes the final reaction in melatonin biosynthesis: converting Normelatonin to melatonin. This reaction is embedded in the more general tryptophan metabolism pathway. The enzyme also catalyzes a second reaction in tryptophan metabolism: the conversion of 5-hydroxy-indoleacetate to 5-methoxy-indoleacetate. The other enzyme which catalyzes this reaction is n-acetylserotonin-o-methyltransferase-like-protein.
N-Acetylserotonin (NAS), also known as normelatonin, is a naturally occurring chemical intermediate in the endogenous production of melatonin from serotonin. It also has biological activity in its own right, including acting as a melatonin receptor agonist, an agonist of the TrkB, and having antioxidant effects.
RAR-related orphan receptor alpha (RORα), also known as NR1F1 is a nuclear receptor that in humans is encoded by the RORA gene. RORα participates in the transcriptional regulation of some genes involved in circadian rhythm. In mice, RORα is essential for development of cerebellum through direct regulation of genes expressed in Purkinje cells. It also plays an essential role in the development of type 2 innate lymphoid cells (ILC2) and mutant animals are ILC2 deficient. In addition, although present in normal numbers, the ILC3 and Th17 cells from RORα deficient mice are defective for cytokine production.
Leptin receptor, also known as LEP-R or OB-R, is a type I cytokine receptor, a protein that in humans is encoded by the LEPR gene. LEP-R functions as a receptor for the fat cell-specific hormone leptin. LEP-R has also been designated as CD295. Its location is the cell membrane, and it has extracellular, trans-membrane and intracellular sections.
Melatonin receptor type 1A is a protein that in humans is encoded by the MTNR1A gene.
G protein-coupled receptor 119 also known as GPR119 is a G protein-coupled receptor that in humans is encoded by the GPR119 gene.
G protein-coupled receptor 50 is a protein which in humans is encoded by the GPR50 gene.
Taste receptor type 2 member 14 is a protein that in humans is encoded by the TAS2R14 gene.
S-arrestin is a protein that in humans is encoded by the SAG gene.
Melatonin receptor 1C, also known as MTNR1C, is a protein that is encoded by the Mtnr1c gene. This receptor has been identified in fish, amphibia, and birds, but not in humans.
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.
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.
TIK-301 (LY-156735) is an agonist for the melatonin receptors MT1 and MT2 that is under development for the treatment of insomnia and other sleep disorders. Its agonist action on MT1 and MT2 receptors in the suprachiasmatic nucleus in the brain enables its action as a chronobiotic. It is in the same class of melatonin receptor agonists as ramelteon and tasimelteon.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.