Physiological effects of melatonin: Role of melatonin receptors and signal transduction pathways

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Abstract

Melatonin, an endogenous signal of darkness, is an important component of the body's internal time-keeping system. As such it regulates major physiological processes including the sleep wake cycle, pubertal development and seasonal adaptation. In addition to its relevant antioxidant activity, melatonin exerts many of its physiological actions by interacting with membrane MT1 and MT2 receptors and intracellular proteins such as quinone reductase 2, calmodulin, calreticulin and tubulin. Here we review the current knowledge about the properties and signaling of melatonin receptors as well as their potential role in health and some diseases. Melatonin MT1 and MT2 receptors are G protein coupled receptors which are expressed in various parts of the CNS (suprachiasmatic nuclei, hippocampus, cerebellar cortex, prefrontal cortex, basal ganglia, substantia nigra, ventral tegmental area, nucleus accumbens and retinal horizontal, amacrine and ganglion cells) and in peripheral organs (blood vessels, mammary gland, gastrointestinal tract, liver, kidney and bladder, ovary, testis, prostate, skin and the immune system). Melatonin receptors mediate a plethora of intracellular effects depending on the cellular milieu. These effects comprise changes in intracellular cyclic nucleotides (cAMP, cGMP) and calcium levels, activation of certain protein kinase C subtypes, intracellular localization of steroid hormone receptors and regulation of G protein signaling proteins. There are circadian variations in melatonin receptors and responses. Alterations in melatonin receptor expression as well as changes in endogenous melatonin production have been shown in circadian rhythm sleep disorders, Alzheimer's and Parkinson's diseases, glaucoma, depressive disorder, breast and prostate cancer, hepatoma and melanoma. This paper reviews the evidence concerning melatonin receptors and signal transduction pathways in various organs. It further considers their relevance to circadian physiology and pathogenesis of certain human diseases, with a focus on the brain, the cardiovascular and immune systems, and cancer.

Introduction

Melatonin (N-acetyl-5-methoxytryptamine) was first isolated and identified by Lerner et al. (1958). It is the major neurohormone secreted during the dark hours at night by the vertebrate pineal gland. Tryptophan serves as the precursor for melatonin biosynthesis, and is taken up from the circulation and then converted into serotonin. Serotonin is then converted into N-acetylserotonin by the enzyme arylalkylamine-N-acetyl transferase (AANAT) while N-acetylserotonin is metabolized into melatonin by the enzyme hydroxyindole-O-methyltransferase (HIOMT) (Axelrod and Wurtman, 1968). Once formed, melatonin is released into the capillaries and in higher concentrations into the cerebrospinal fluid (Tricoire et al., 2003) and is then rapidly distributed to most body tissues (Cardinali and Pevet, 1998).

Intravenously administered melatonin exhibits a biexponential decay with a first distribution half-life of 2 min and a second metabolic half-life of 20 min (Claustrat et al., 2005). Circulating melatonin is metabolized mainly in the liver where it is first hydroxylated by cytochrome P450 monooxygenases and then conjugated with sulfate to form 6-sulfatoxymelatonin (Skene et al., 2001). Melatonin is also metabolized by oxidative pyrrole-ring cleavage into kynuramine derivatives (Hirata et al., 1974). The primary cleavage product is N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), which is deformylated, either by arylamine formamidase or hemoperoxidases to N1-acetyl-5-methoxykynuramine (Hardeland et al., 1993, Tan et al., 2007). Some evidence has suggested that pyrrole ring cleavage contributes to about one-third of the total melatonin catabolism, but the percentage may be even higher in certain tissues. It has been proposed that AFMK is the primitive and primary active metabolite of melatonin (Tan et al., 2007).

The circadian pattern of pineal melatonin secretion is regulated by the biological clock that resides in mammals within the hypothalamic suprachiasmatic nucleus (SCN) of the hypothalamus. Lesions in the SCN abolish the rhythm of pineal melatonin production in mammals (Klein and Moore, 1979). The SCN is synchronized to the environmental light–dark cycle by light perceived by the retina, acting mainly on a subgroup of retinal ganglion cells (RGCs) that contain the photopigment melanopsin (Berson et al., 2002). These RGCs connect to the SCN via the retinohypothalamic tract.

The SCN regulates pineal gland's function through a polysynaptic network involving the paraventricular nucleus of the hypothalamus. Descending polysynaptic fibers from these regions project through the medial forebrain bundle and the reticular formation to the intermediolateral horns of the cervical segments of the spinal cord (Buijs et al., 1998). Postganglionic sympathetic fibers from the superior cervical ganglia reach the pineal gland and regulate melatonin biosynthesis through the presynaptic release of norepinephrine (NE). NE release occurs during the “night” portion of the circadian pacemaker cycle provided that this occurs in a dark environment.

Activation of the pineal β-adrenergic receptors by NE results in increased 3′,5′-cyclic adenosine monophosphate (cAMP) concentration that promotes the biosynthesis of melatonin (Klein et al., 1971). α1-Adrenergic receptors potentiate β-adrenergic activity by producing a sharp increase in intracellular Ca2+ and activation of protein kinase C (PKC) and of prostaglandin synthesis (Vacas et al., 1980, Ho and Klein, 1987, Krause and Dubocovich, 1990). The subcellular mechanisms involved in increase and turnoff of AANAT activity have been elucidated in great detail [see for references Maronde and Stehle, 2007]. Cyclic AMP stimulates AANAT expression and phosphorylation via protein kinase A, which also allows AANAT to be stabilized by binding of 14-3-3 proteins (Schomerus and Korf, 2005, Ganguly et al., 2005). The nocturnal exposure to bright light suppresses melatonin production immediately by degradation of pineal AANAT (Gastel et al., 1998).

It has now been demonstrated that melatonin is produced by many organs other than the pineal gland. These include the retina (Cardinali and Rosner, 1971a, Cardinali and Rosner, 1971b, Tosini and Menaker, 1998), gastrointestinal tract (Raikhlin and Kvetnoy, 1976, Bubenik, 2002), skin (Slominski et al., 2005), lymphocytes (Carrillo-Vico et al., 2004) and bone marrow (Conti et al., 2000).

Because pineal melatonin production occurs during the dark phase and is acutely suppressed by light, and, further, because melatonin is quickly cleared from the circulation following the cessation of its production, the time and duration of the melatonin peak reflect the environmental night period (Cardinali and Pevet, 1998). Plasma melatonin exhibits a circadian rhythm with high levels at night, and low levels during the day, attaining peak concentrations of plasma melatonin between 02:00 and 04:00 h. Longer nights are associated with a longer duration of melatonin secretion (Cardinali and Pevet, 1998). Hence melatonin is a signal of darkness that encodes time-of-day and length-of-day information to the brain including the SCN, brain and peripheral organs (Pandi-Perumal et al., 2006b). In mammals, melatonin is critical for the regulation of seasonal changes for various physiological, neuroendocrine and reproductive functions (Reiter, 1980, Cardinali and Pevet, 1998). These actions of melatonin are processed in nuclei of the hypothalamus and in the pars tuberalis (PT) of the pituitary (Lincoln, 2006). These particular functions appear to be less relevant to humans and will therefore not be considered further in this review.

The other major function of melatonin is its regulation of the phase of circadian rhythms by a direct action on the SCN (Gillette and Tischkau, 1999). Melatonin administration has been shown to shift circadian rhythms in both rodents (Redman et al., 1983) and humans (Arendt and Skene, 2005, Cardinali et al., 2006). When administered once daily at the normal bedtime hour, melatonin (at doses ranging from 0.5 mg to 5 mg) entrains free running circadian rhythms of most blind subjects, and improves nocturnal sleep and daytime alertness (Arendt and Skene, 2005). The observations have been confirmed in other studies also (Lockley et al., 1995, Sack et al., 2000). In sighted subjects, melatonin has also been shown to maintain entrainment at a 5 mg dose (Middleton et al., 1997).

The timing of melatonin secretion is closely associated with the timing of sleep propensity and it also coincides with decreases in core body temperature, alertness and performance (Dijk and Cajochen, 1997, Rajaratnam and Arendt, 2001, Arendt, 2006). Melatonin has the capacity to alter the timing of mammalian circadian rhythms and functions in concert with light to synchronize circadian rhythms with the prevailing light–dark cycles. It has been used successfully in treating various circadian rhythm disorders such as delayed sleep phase syndrome (Dahlitz et al., 1991), shift-work sleep disorder (Folkard et al., 1993, Burgess et al., 2002, Srinivasan et al., 2006b), blindness or pathophysiological states of delayed/advanced sleep phase syndromes (Hagan and Oakley, 1995, Zisapel, 2001a, Arendt and Skene, 2005, Lewy et al., 2006, Cardinali et al., 2006).

Melatonin is reported to have a role in sleep initiation as the trigger for opening the circadian “sleep gate”, acting as a sleep regulator (Shochat et al., 1997, Krauchi and Wirz-Justice, 2001, Zhdanova and Tucci, 2003, Pandi-Perumal et al., 2005, Dijk and von Schantz, 2005, Zisapel, 2007). Other actions of the hormone include inhibition of dopamine (DA) release in the hypothalamus and retina (Zisapel, 2001b), involvement in the aging process (Reiter et al., 1998, Karasek, 2004) and pubertal development (Waldhauser et al., 1988, Silman, 1991, Cavallo, 1992, Commentz et al., 1997, Salti et al., 2000), blood pressure control (Arangino et al., 1999, Cagnacci et al., 2001, Cavallo et al., 2004, Scheer et al., 2004, Grossman et al., 2006), free-radical scavenging (Tan et al., 2007) and regulation of the immune response (Srinivasan et al., 2005, Carrillo-Vico et al., 2006). If given during the day, when it is not present endogenously, melatonin has soporific effects which resemble its action at night, i.e., it lowers body temperature and induces fatigue while concomitantly producing a brain activation pattern resembling that which occurs during sleep (Gorfine et al., 2006, Gorfine et al., 2007, Gorfine and Zisapel, 2007).

Melatonin production decreases with age and in certain diseases, e.g., certain malignancies, Alzheimer's disease (AD) and cardiovascular disease (Brugger et al., 1995, Bartsch and Bartsch, 1999, Girotti et al., 2000, Girotti et al., 2003, Zhou et al., 2003, Jonas et al., 2003, Pandi-Perumal et al., 2005). This decrease in melatonin output has been linked to insomnia in older patients (Haimov et al., 1994, Leger et al., 2004) and to a higher prevalence of cancer (Bartsch and Bartsch, 2006, Stevens, 2006, Schernhammer et al., 2006).

In this review, we will focus our attention on melatonin receptors and signal transduction pathways and their role in circadian physiology and pathogenesis of certain human diseases. For an in-depth discussion of other important functions of melatonin the reader is referred to recent reviews of its direct and indirect actions as an antioxidant (Hardeland, 2005, Reiter et al., 2007, Tan et al., 2007).

An important conceptual difficulty in melatonin research is that it is a signal of darkness, but has different functional consequences depending on the species’ time of peak activity. In nocturnal species, melatonin is associated with arousal and physical activity whereas in diurnal species, it is associated with sleep and rest. Accordingly, administration of melatonin promotes sleep in humans (Dollins et al., 1994), but not in rats and mice (Huber et al., 1998, Mailliet et al., 2001). Because the SCN has a similar function in nocturnal and diurnally active animals, the differential “interpretation” of the melatonin signal must be downstream to the SCN, and possibly involves a counter-balance between melatonin's effects on brain regions that are involved in certain activities (e.g., arousal) and those involved in suppression of those activities. Similar considerations must be applied to different tissues and functions of melatonin in the body. Therefore, when applicable, the effects on human tissues and mechanisms are highlighted.

Section snippets

Melatonin receptors, their localization and regulation

Two mammalian subtypes of G protein coupled melatonin receptors, MT1 (Mel 1a) and MT2 (Mel 1b), have been cloned and characterized (Reppert et al., 1994, Reppert et al., 1995, Dubocovich and Markowska, 2005). The human MT2 receptor has a lower affinity (Kd = 160 pmol/l) for 125I-melatonin as compared to the human MT1 receptor (Kd = 20–40 pmol/l), but the binding characteristics of the two are generally similar, e.g., both are of high affinity and the agonist binding is guanosine triphosphate

Melatonin's signal transduction mechanisms

The signal transduction pathways for melatonin receptors appear to vary among different tissues and cell types [for reviews, see von Gall et al., 2002, Witt-Enderby et al., 2003 and references cited therein]. By using recombinant melatonin receptors it has been shown that the MT1 melatonin receptor is coupled to different G proteins that mediate adenylyl cyclase inhibition and phospholipase C beta activation. Thus MT1 receptor activation leads to activation of a large variety of G proteins

Melatonin receptors in the suprachiasmatic nuclei

The physiological role of melatonin in the SCN has been studied in a number of animal models. Melatonin inhibits SCN multiunit activity by acting through MT1 receptors (Liu et al., 1997). This effect is more pronounced during daytime when SCN neuronal activity is high, although it is also observed at night. The acute inhibitory effect of melatonin on SCN multiunit activity is absent in MT1 receptor knockout mice (Liu et al., 1997). Expression of the MT1 receptor has been reported in the human

Melatonin receptors in the eye

In the eye, melatonin is synthesized by a metabolic pathway which is similar to that which occurs in the pineal gland. The first description of melatonin biosynthetic capacity in the mammalian retina was made in 1971 by Cardinali and Rosner, 1971a, Cardinali and Rosner, 1971b, who described the presence of HIOMT activity and the conversion of labeled serotonin into melatonin by the rat retina. Subsequent studies confirmed and extended those observations (Tosini and Menaker, 1998, Liu et al.,

Melatonin receptors in the hippocampus

Melatonin binding sites exist in the hippocampus of several mammals. MT1 and MT2 receptors were localized in the dentate gyrus, CA3 and CA1 regions and subiculum of the hippocampus (Musshoff et al., 2002). Melatonin (1 μM) has been found to enhance the firing rate of neurons in the CA1 regions, an effect suppressed by the simultaneous administration of the MT2 receptor antagonist luzindole (Musshoff et al., 2002). In murine hippocampal slices, melatonin induced a concentration-dependent

Melatonin receptors in other brain areas

MT1 and MT2 receptors are expressed in the cell bodies of granule cells and basket-stellate cells of the human cerebellar cortex and have been found to be co-localized with glutamatergic synapses (Mazzucchelli et al., 1996, Al Ghoul et al., 1998). The possible significance of melatonin for posture control and balance has been discussed (Fraschini et al., 1999).

MT1 receptors have been localized in other areas of the brain such as the prefrontal cortex, caudate-putamen, substantia nigra, ventral

Melatonin receptors in the cardiovascular system

Patients with coronary heart disease and non-dipper hypertensive patients (patients who do not exhibit a normal decline in blood pressure at night) have significantly lower nocturnal melatonin secretion than healthy controls (Brugger et al., 1995, Girotti et al., 2000, Yaprak et al., 2003, Jonas et al., 2003). Melatonin receptors (both MT1 and MT2) have been identified in the human coronary arteries of healthy human subjects and patients suffering from coronary heart disease (Ekmekcioglu et

Melatonin receptors in the immune system

Melatonin is immunomodulatory in both animals and in humans (Maestroni, 2001, Srinivasan et al., 2005). Inhibition of melatonin synthesis for instance suppresses both cellular and humoral responses in mice (Maestroni et al., 1986).

The immunomodulatory role of melatonin is related in part to its action on specific melatonin receptors located in immunocompetent cells (Maestroni et al., 2002). Melatonin also regulates hematopoiesis through its action on specific receptors on bone marrow cells (

Breast cancer

Ever since Bartsch et al. (1981) showed that compared to healthy controls, Indian women with advanced breast cancer had diminished urinary levels of melatonin, a number of functional studies have shown a relationship between melatonin and human breast cancer. Tamarkin et al. (1982) found that compared to age matched controls, the normal nocturnal increase in the plasma concentration of melatonin in women with estrogen-receptor (ER) positive breast tumors was significantly reduced and further

Conclusions

Evidence obtained from a number of studies indicates that melatonin exerts its physiological action in many areas of the CNS, such as the SCN, hippocampus, dopaminergic pathways, prefrontal cortex and cerebellum, by acting through G protein coupled membrane MT1 or MT2 receptors. MT1 and MT2 receptors in the SCN and hippocampus and melatonin's physiological activities in these areas implicate these receptors in the regulation of sleep and circadian rhythms and perhaps memory consolidation. The

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