Melatonin Receptors

The hormone melatonin is produced primarily in the mammalian pineal gland and retina following a circadian rhythm with high levels being released at night. The circadian secretion of melatonin is controlled by the master biological clock located within the suprachiasmatic nucleus of the hypothalamus and synchronized to a 24 hour cycle by the daily photoperiod. In mammals, melatonin has been implicated in the regulation of sleep, circadian rhythms, retina physiology, cardiovascular and immune function and cancer cell growth. These effects of melatonin appear to be mediated, at least in part, through activation of high affinity G protein-coupled melatonin receptors. However, an action of melatonin as a ligand for putative nuclear melatonin receptors, as a calmodulin antagonist, inhibitor of NO production, scavenger of free radicals and an antioxidant cannot be excluded at the present time.

Membrane-associated melatonin receptors were originally classified based on kinetic properties and pharmacological profiles into the ML1 and ML2 classes with 2-[125I]-iodomelatonin binding affinities in the picomolar and nanomolar range, respectively. cDNA'€™s encoding melatonin receptors with the ML1-like pharmacology profile (i.e., 2-iodomelatonin > melatonin > 6-chloromelatonin > N-acetylserotonin >> serotonin) were cloned (Mel1a, Mel1b, Mel1c) in several vertebrate species including humans. These receptors are coupled to pertussis toxin-sensitive G proteins, and are members of a new subfamily of G protein-coupled receptors. The mammalian melatonin receptors are now referred as MT1 (formerly Mel1a) and MT2 (formerly Mel1b). The MT1 and MT2 melatonin receptors exhibiting 60% amino acid homology, show different molecular structure, distinct chromosomal localization and pharmacological profile. The Mel1c, originally cloned from Xenopus laevis melanophores, is not found in mammals.

The competitive melatonin receptor antagonists luzindole and S20928 as well as MT2 selective melatonin receptor antagonists (e.g. 4P-ADOT and 4P-PDOT) allowed identification of several functional responses for melatonin. The presynaptic melatonin receptor modulating dopamine release from retina shows the pharmacology of the MT2 melatonin receptor. In the rat suprachiasmatic nucleus slice preparation, activation of the MT1 receptor inhibits neuronal firing while activation of the MT2 melatonin receptor phase shifts the peak of circadian rhythm of neuronal activity. Melatonin appears to mediate dual responses in mammalian arteries possible through activation of the MT1 (e.g., vasoconstriction) and MT2 (i.e., vasodilation) melatonin receptors.

The putative MT3 (formerly ML2) type of melatonin receptor binds 2-[125I]-iodomelatonin with nanomolar affinity, displays a distinct pharmacological profile (i.e., 2-iodomelatonin > 6-chloromelatonin > N-acetylserotonin > melatonin >> serotonin), and is coupled to the stimulation of phosphoinositide turnover. This binding site was originally thought to be a G protein-coupled receptor; however, recently a protein from hamster kidney, subsequently identified as quinone reductase II, was found to bind 2-[125I]-iodomelatonin while demonstrating the same pharmacology as the putative MT3 melatonin receptor site. Specific 2-[125I]-iodomelatonin binding to MT3 binding sites were absent in brain and kidney membranes from mice with genetic deletion of quinone reductase 2. The physiological responses associated with these putative MT3 sites are not known.

Together the use of melatonin receptor specific and receptor selective analogs is essential to unravel the signaling pathways and the associated neuroendocrine and functional responses to melatonin in mammals. The use of MT1, MT2 and MT3 melatonin receptor agonists and antagonists will help to further elucidate the mechanism(s) of melatonin’s action in mammals and may prompt the development of selective analogs for the treatment of insomnia and circadian sleep and mood disorders.

 

The Table below contains accepted modulators and additional information.

 

Currently Accepted Name MT1 MT2 MT3
Previous Names Mel1a
ML1A
MEL1A
Mel1b
ML1B
MEL1B
ML2
Structural Information 350 aa (human) 363 aa (human) Not Known
Full Agonists Melatonin (M5250)
2-Iodomelatonin
N-Propionyl melatonin
N-Butanoyl melatonin
6-Chloromelatonin
2-Methyl-6,7-dichloromelatonin
S-20098 (A1362)
GR 196429
8M-PDOT
(–€“)-AMMTC
S26131
Melatonin (M5250)
2-Iodomelatonin
N-Propionyl melatonin
N-Butanoyl melatonin
6-Chloromelatonin
2-Methyl-6,7-dichloromelatonin
S-20098 (A1362)
GR 196429
8M-PDOT
(–€“)-AMMTC
IIK7 (I5531)
Melatonin (M5250)
2-Iodomelatonin
6-Chloromelatonin
N-Acetylserotonin (A1824)
5-MCA-NAT
Partial Agonists 5-Methoxyluzindole
N-Acetyltryptamine (A7342)
5-Methoxyluzindole
N-Acetyltryptamine (A7342)
Not Known
Antagonists Luzindole (L2407)
S20928
Luzindole (L2407)
S20928
4P-PDOT
4P-ADOT
K185 (K1888)
Luzindole (L2407)
Prazosin (P7791)
N-Acetyltryptamine (A7342)
Signal Transduction Mechanisms Gi (cAMP modulation)
Gq/11 (increase IP3/DAG)
Gi (cAMP modulation)
cGMP modulation
Gq/11 (increase IP3/DAG)
Radioligands of Choice 2-[125I]-Iodomelatonin
[3H]-Melatonin
2-[125I]-Iodomelatonin
[3H]-Melatonin
2-[125I]-Iodomelatonin
2-[125I]-MCA-NAT
Tissue Expression Suprachiasmatic nucleus, retina, cerebellum, arteries, pars tuberalis Suprachiasmatic nucleus, retina, cerebellum, arteries Brain, kidney, testis
Physiological Function Inhibition Neuronal firing, inhibition Prolactin secretion, vasoconstriction Phase shift circadian rhythms, of neuronal firing, inhibition, dopamine release, vasodilation Not Known
Disease Relevance Insomnia Phase shift circadian rhythms, increase immune function Decrease intraocular pressure

 

Abbreviations

4P-ADOT: 4-Phenyl-2-acetamidotetralin
(–)-AMMTC: N-Acetyl-4-aminomethyl-6-methoxy-9-methyl-1,2,3,4-tetrahydrocarbazole
4P-CADOT: 4-Phenyl-2-chloroacetamidotetralin
GR 196429: N-[2-[2,3,7,8-Tetrahydro-1H-furo(2,3-g)indol-1-yl]ethyl]acetamide
IIK7: N-Butanoyl-2-(2-methoxy-6H-isoindolo[2,1-a]indole-11-yl)ethanamine
K185: N-Butanoyl-2-(5,6,7-trihydro-11-methoxybenzo[3,4]cyclohept[2,1-a]indol-13-yl)ethanamine
Luzindole: 2-Benzyl-N-acetyltryptamine
5-MCA-NAT: 5-Methoxycarbonylamino-N-acetyltryptamine
Melatonin: 5-Methoxy-N-acetyltryptamine
4P-PDOT: 4-Phenyl-2-propionamidotetralin
8M-PDOT: 8-Methoxy-2-propionamidotetralin
S-20098: N-[2-(7-Methoxy-1-naphthalenyl)ethyl]acetamide
S20928: N-[2-Naphth-1-yl-ethyl]-cyclobutyl carboxamide
S26131: N-(2-{7-[3-({8-[2-Acetylamino)ethyl]-2-naphtyl}oxy)propoxy]-1-naphthyl}ethyl)acetamide

 

References