A Neuroendocrine Transducer of Light Information

Anamika Sengupta and Gianluca Tosini

Circadian Rhythms and Sleep Disorders Program
Neuroscience Institute and Department of Pharmacology and Toxicology
Morehouse School of Medicine, Atlanta, GA 30310

The Pineal Gland (epiphysis cerebri in mammals), conferred as "the seat of Human soul" by Rene Descartes in 17th century, was considered as an epithalamic appendage of the vertebrate brain, and a vestigial evolutionary element until the 19th century. The endocrine aspect of the pineal gland reported in the early 20th century was confirmed through isolation of the hormone melatonin by Aaron B. Lerner in 1958. The pineal thus attracted scientific attention in the late 20th century due to its crucial role of transducing photoperiodic information through the rhythmic secretion of the daily and annual timekeeping hormone melatonin. It is now confirmed to be the neuroendocrine transducer of photic information into an endocrine response through the synthesis and release of the hormone melatonin.

Functional Organization of the Pineal Gland Exhibits a Unique Evolutionary Trend
The pineal gland develops from the roof of the embryonic forebrain and in adult brain. The pineal, together with habenula and the stria medullaris, constitutes the epithalamus. Evolutionary trends leading to the progressive replacement of direct photosensitivity (characteristic of non-mammalian vertebrates) by indirect photosensitivity (characteristic of mammals) have led to dramatic changes in the structure and function of the pineal gland (Falcon et al., 2009). The pineal gland of non-mammalian vertebrates is primarily composed of pinealocytes, which are structurally analogous to retinal cones, lower order neurons and interstitial glial cells (Collins et al., 1989; Falcon, 1999). The organization of the pineal in these animals resembles the vertebrate retina, albeit with much less complexity (Ekstrom and Miessl, 1997; Falcon 1999), and is indicative of its role as a luminance detector (Ekstrom and Miessl, 1997). In the mammalian pineal, the pinealocytes have lost the capability to directly respond to light, and their major function is the synthesis of melatonin (Falcon, 1999). However, it is worth noting that in neonatal rats and/or hamsters, the pinealocytes develop photoreceptor like characteristics that disappear after postnatal development birth (Clabough 1973; Zimmerman and Tso 1975). A series of studies have also shown that much of the photoreceptive machinery is still present in the pineal of neonatal mammals (Blackshaw and Snyder,1997), and that the pineal of neonatal rats may be capable of direct photosensitivity in vivo (Zweigg et al., 1966; Machado et al., 1969) and in vitro (Tosini et al., 2000; Fukuhara and Tosini 2003). Finally, it has also been suggested that melanopsin may mediate the photosensitivity observed in the neonatal pineal (Saafir et al., 2006). The reason why the mammalian pineal has lost the capability to directly respond to light is unknown, but it is believed to be a consequence of the evolutionary history of mammals (Menaker et al., 1997).

Melatonin Synthesis in the Pineal Gland
The pineal hormone melatonin is primarily synthesized in the pineal gland at night regardless of the diurnal or nocturnal activity of the animals. The initial step of the biosynthesis of this indoleamine involves the uptake of its precursor L-tryptophan from the circulation into the pinealocytes, followed by its conversion into 5-hydroxytryptophan by tryptophan hydroxylase. Further decarboxylation by L-aromatic aminoacid decarboxylase forms 5 hydroxytryptamine, also called serotonin. Acetylation of serotonin by serotonin N-acetyltransferase, also known as arylalkylamine N-acetyltransferase (AA-NAT), forms N-acetyl serotonin (NAS). Finally, methylation of N-acetylserotonin by hydroxyindole-O-methyltransferase (HIOMT) forms the final product melatonin (Figure 1). AA-NAT, the rate limiting enzyme for melatonin synthesis, activity is regulated at the transcriptional and post transcriptional levels (Klein et al., 1997; Gastel et al., 1998; Klein, 2007). In rats, pineal Aa-nat transcription and activity are up-regulated at night (100-fold more than during the day). By contrast, in monkeys and sheep, changes in the AA-NAT activity occurs at the protein level with small changes in the level of Aa-nat transcription (Coon et al., 1995; 2002).

Figure 1. Biosynthesis of melatonin from tryptophan in mammalian pinealocytes.

The suprachiasmatic nuclei (SCN) of the hypothalamus via a sympathetic multisynaptic pathway regulates rhythmic melatonin synthesis by acting on Aa-nat transcription (Klein et al., 1983; Tessonneaud et al., 1995; Garidou et al., 2002; Perreau-Lenz et al., 2005). The SCN uses a combination of daytime inhibitory and nighttime stimulatory signals to control the daily rhythm of pineal melatonin synthesis (Perreau-Lenz et al., 2003, 2004). At night the sympathetic neurotransmitter, Norepinephrine (NE), is released from the postganglionic nerve terminals innervating the pineal, thus stimulating (ß1 and 1 adrenoreceptors on the pinealocytes, leading to an increase in intracellular calcium levels. This potentiates activation of adenylyl cyclase (AC) by a mechanism that involves protein kinase C (PKC) and calcium calmodulin protein kinase, followed by a 100-fold increase in intracellular levels of cAMP. High cAMP at night activates protein kinase A (PKA), which then phosphorylates AA-NAT, which forms a complex with 14-3-3 proteins (Fu et al., 2000), which protects it from dephosphorylation and denaturation, thus elevating melatonin synthesis in the pinealocytes (Ganguly et al., 2001; Schomerus and Korf 2005). Recent studies have also shown that the removal of the SCN results in a daytime increase in Aa-nat mRNA levels, suggesting that the presence of an inhibitory SCN output contributs to the control of pineal melatonin rhythm (Kalsbeek et al., 2000). It has also been suggested that the GABA-ergic output of the SCN terminals on to the pre-autonomic PVN neurons may be the daytime inhibitory signal contributing to the morning decline of melatonin synthesis (Kalsbeek et al., 2000).

Another important factor in the regulation of the melatonin level is represented by light. Light is the dominant environmental factor that regulates melatonin biosynthesis in vertebrates, and regardless of whether a species is diurnal/nocturnal or exhibits crepuscular activity, pineal melatonin levels are high during the dark phase of a natural or imposed illumination cycle (Reiter, 1991; Arendt, 1999). Exceptions to this rule are the retinal melatonin levels of Salmonoid fish (Iguchi et al., 1981; Arendt, 2005). Light signals perceived by the retina are conveyed via the retinohypothalamic tract to the SCN, and then to the mammalian pineal gland via the previously mentioned pathway (Korf et al., 1998; Korf, 1999). Light exerts a distinct suppressive effect on melatonin production irrespective of whether it is full spectrum white light, monochromatic light or UV-A light. The amount of light required to suppress melatonin production at night varies with species, previous light exposures, and the particular time of the night (Bojkowski et al., 1987; Brainard et al., 1988, 2001). Blue light (446-477 nm) is the most effective light to suppress melatonin (Brainard et al., 2001), thus suggesting that the intrinsically photosensitive retinal ganglion cells (ipRGCs) are involved in this phenomenon (Paul et al., 2009). Another important factor involved in the regulation of melatonin synthesis and levels is age. Melatonin or 6-sulphatoxtmelatonin levels in humans, barely detectable after birth, attains a robust rhythm between 6-8 weeks of age (Kennaway et al., 1992), followed by a rapid increase during puberty, and then a steady decrease during adulthood (Waldhauser et al., 1991; Karasek, 2004).

Metabolism of Melatonin
Once melatonin has been synthesized by the pinealocytes it freely diffuses out. Due to its amphiphilic nature, it can easily cross the blood brain barrier to enter the CNS and/or the general circulation (Hardeland, 2009; Leston et al., 2009). Several concurrent pathways are involved in the metabolism of melatonin. Melatonin in the CNS is metabolized by various isoforms of cytochrome P450 monooxygenase enzymes (CYPs) present in the brain (Ma et al., 2005; Pandi-Perumal et al., 2006). Isoforms of these enzymes (CYP1A2, CYP2C19) may either demethylate melatonin into NAS, or hydroxylation of melatonin into 6 hydroxymelatonin (through CYP1A1, CYP1B1) may occur, which may then be conjugated with sulphates to form 6-sulphatoxymelatonin. In the pineal gland melatonin, is deacetylated to 5-methoxytryptamine (5-MT; Rogowski et al., 1979; Beck and Jonsson 1981) with the help of enzymes called Aryl acrylamidases (AAAs), although 5-MT can be formed from serotonin also. The 5-MT is catabolised by monoamine oxidase in the pineal (Raynaud and Pevet, 1991). The third metabolic pathway is the kynurenine pathway (30% of overall melatonin metabolism) involving enzymes like myeloperoxidase, indoleamine 2, 3 dioxygenase and other non-enzymatic oxidants, which cleave the pyrrole ring of melatonin forming N1-acetyl-N2-formyl-5-methoxykinuramine (AFMK) and N1-acetyl-5-methoxy-kynuramine (AMK) (Hirata et al., 1974) These metabolic biproducts of melatonin help in scavenging reactive oxygen and nitrogen species, act as a mitochondrial modulator and regulator of cyclooxygnase-2 (Tan et al., 2001; Hardeland et al., 2009; Hardeland, 2010). The metabolized forms of melatonin, along with a small amount of unmetabolized melatonin, are excreted through the urine.

Melatonin Acts via G-Protein-Coupled Receptors
Melatonin is known to have autocrine and paracrine effects on various cell types and peripheral tissues. Such effects studied in vitro and in vivo have been found to be dependent on specific melatonin receptors (Jockers et al., 2008). In mammals, melatonin receptors so far identified include G protein-coupled melatonin receptor type 1 (MT1) and type 2 (MT2) (Reppert, 1997; Figure 2). Recent studies have also identified MT3 as quinone reductase 2, a detoxifying enzyme having functional homology with other quinone reductases in human tissues (Nosjean et al., 2000). The role played by MT3 in is still unclear.

Figure 2. Pathways activated by MT1 and MT2 receptor signaling. Both Melatonin receptors are negatively coupled with adenylyl cyclase (AC) and the activation of these receptors decrease cAMP. Mel = melatonin; K= potassium; BK= Big Potassium channels; PKA = Protein kinase A; cAMP = Cyclic adenosine monophosphate; P-CREB = phosphorilated-cAMP response element-binding element; PLC= Phospholipase C; DAG = diacylglycerol; PKC = Protein kinase C; GC = Guanylate cyclase; cGMP = Cyclic guanosine monophosphate.

The binding characteristics of MT1 and MT2 receptors are almost the same, MT2 having a kD value about 3 times lower than that of MT1. The distribution of MT1 and MT2 receptors in mammals is variable. MT1 and MT2 receptors are widely distributed in the body (Whitt-Enderby et al., 2003; Luchetti et al., 2010). MT1 is a 350 amino acid long protein exhibiting 60% structural homology with the 362 amino acid long MT2 receptor protein (Reppert, 1997). Both of the melatonin receptors have 7 transmembrane alpha helices with 4 intracellular and 4 extracellular domains, characteristic features of all G protein coupled receptors in mammals. Recent studies on the detailed structural properties of melatonin receptors (Rivara et al., 2005; Chugunov et al., 2006; Farce et al., 2008; Mazna et al., 2008 ) show that the dimensions of the putative ligand binding site, which lies on TM5 in both the receptors, is found to be relatively smaller in the case of MT1, when compared to MT2. This dissimilarity between the two melatonin receptors affects their binding affinity (Luchetti et al., 2010). The residues in the C terminal region of the MT receptors, specifically, TM7 exposed to the cytoplasmic face of the target cell, is the site for G protein binding (Jockers et al., 2008) and for the interaction with intracellular proteins. Proteins like filamin A (insulin receptor substrate 4) are common members of MT1 and MT2 associated complex (Daulat et al., 2007). Small GTPases like Rac1, Rap1A, 2',3'-cyclic nucleotide, 3' phosphodiesterase, protein elongation factor, 1-gamma, forms specific complexes with MT1 subtype, while catenin, delta-1, protein phosphatase (PP) 2C-gamma interacts specifically with MT2 (Daulat et al., 2007). The C terminal tails for both MT receptors contain a single cysteine residue (C7.72 and C7.77 for MT1 and MT2, respectively), essential for adenylate cyclase activity inhibition, while a Tyr residue, Y7.64, is found to influence receptor activity and internalization (Sethi et al., 2008). Phosphorylation sites of PKA, PKC and casein kinase 1, 2 are found in the C terminal cytoplasmic domain (Dubocovich and Markowska, 2005).

The AC/cAMP/PKA/CREB pathway is activated by melatonin binding to MT1 receptors (Jockers et al., 2008; Figure 2). A classical example of the involvement of this downstream signaling pathway is reflected in the acute endocrine effects of melatonin on the pars tuberalis of the pituitary (Fustin et al., 2009). Activation of MT1 receptor by melatonin increases the phosphorylation of mitogen activated protein kinase 2 (MEK2), extracellular signal-regulated kinases 1 and 2 (EKR1 and ERK 2) (Witt-Enderby et al., 2000), and c-jun-N-terminal kinase (JNK) via pertussis toxin sensitive and insensitive G protein (Chan et al., 2002).

The activation of MT2 receptors by the binding of its ligand inhibits forskolin stimulated cAMP production (Reppert et al., 1995; MacKenzie et al., 2002), thus stimulating phosphoinositide turnover (Chan et al., 2002; MacKenzie et al., 2002). Stimulation of phosphoinositide turnover by activation of the ßγ subunit of pertusis-toxin sensitive G protein by MT1 receptors has also been reported (Godson and Reppert, 1997; Roka et al., 1999). The GC/cGMP pathway is inhibited by MT2 receptor activation (Hernandez-Pacheko et al., 2008; Figure 2).

Melatonin signaling is hypothesized to be influenced by homo and heterodimerization of the MT1 and MT2 receptors (Levoye et al., 2006a; Jockers et al., 2008), and the coupling of these receptors to other G protein coupled receptors like GPR50 (G protein coupled orphan receptor 50), which have high homology with melatonin receptors, but designated as orphan receptors as they do not bind to melatonin, and their endogenous ligand is unknown (Jockers et al., 2008). They heterodimerize with MT1 and MT2, abolishing high affinity agonist binding and G protein coupling to MT1 (acting as MT1 agonist), but does not influence MT2 receptors (Levoye et al., 2006b).

Pineal Involvement in the Modulation of Circadian Rhythms
Melatonin acts as a chronobiotic molecule (Pevet et al., 2006), stabilizing or re-enforcing the circadian rhythms of body functions in mammals like rodents (Armstrong, 1989). Human studies on the phase shift of circadian rhythms of body functions, such as body temperature and sleep-wake cycle, are affected by melatonin. Phase advances follow the evening administration of melatonin, while phase delays follow morning administration (Lewy et al., 1992; Cajochen et al., 2003). Timed administration of melatonin has been shown to facilitate readjustments after acute phase shifts of the light-dark cycle, e.g., jet lag (Arendt et al., 1997). The chronobiotic effect of melatonin on circadian rhythms can be attributed to the influence of melatonin on the metabolic and electrical activity of the SCN, as shown in several in vitro and in vivo studies (Pevet et al., 2006; Kudo et al., 2007). Melatonin differentially influence the expression of an array of clock genes, notably Period (Per1, 2, 3) and Cryptochrome (Cry1, 2), which are expressed in the pars tuberalis and SCN (Lincoln et al., 2003; Agez et al., 2009). The activation of Per genes occurs during the early day, when melatonin levels are low, and the activation of Cry occurs during the early night, when melatonin levels are raising (Lincoln et al., 2003). The pattern of melatonin secretion conveys photoperiodic information to the pars tuberalis, which in turn influences the pattern of expression of the Per and Cry genes, translating the melatonin signal for entraining body rhythms (rhythmic synthesis and secretion of hormone) to the light phase of the external environment (Walton et al., 2011). These effects are melatonin and pineal dependent. A pinealectomy or the removal of MT1 receptors abolish such rhythms in the pars tuberalis (Messager et al., 2001; Von Gall et al., 2002).

Regulation of the Sleep-Wake Cycle
The sleep-wake cycle is regulated by the interaction of endogenous circadian and homeostatic processes in the body. Circadian rhythm sleep disorders arise when there is a misalignment between the timing of the endogenous circadian rhythms and the external environment, or when there is dysfunction of the circadian clock or its entrainment pathways (Dodson and Zee, 2010). Research over the last decade has established a strong relationship between melatonin levels and sleep homeostatic mechanisms in humans (Rajaratnam et al., 2004). The quality of sleep declines drastically with aging, as do the nocturnal levels of melatonin in humans (Pandi-Perumal et al., 2005). Moreover, patients with insomnia or experimental animals induced with insomnia (rapid wakefulness and inability to sleep between 2 a.m - 3 a.m) or narcolepsy or hyperactive disorder in children, can be corrected by the administration of pharmacological oral doses of melatonin ranging between 5-50 mg (Cardinali et al., 2002). Administration of melatonin at bedtime is found to resynchronize circadian rhythms with sleep function, thus promoting sleep (Cardinali et al., 2002; Arendt, 2003). Sleep disturbances associated with jetlag can be corrected by the oral administration of melatonin during bedtime between 10 pm and midnight (Brzezinski et al., 2005). Thus, from these reports we can conclude that the timed administration of exogenous melatonin can be useful in the treatment of certain circadian rhythm sleep disorders, including delayed sleep phase, advanced sleep phase, free-running, and irregular sleep-wake cycle.

However, the role of endogenous melatonin in the regulation of the sleep-wake cycle in mammals is still questionable. Surgical pinealectomy in rats housed under a 12:12 light-dark cycle did not affect REM or NREM sleep (Rechtschaffen et al., 1969), although pinealectomised rats housed in constant darkness exhibited a decrease in the amplitude of the circadian rhythm of REM and NREM sleep (Kawakami et al., 1972). Such studied indicate that circulating endogenous melatonin may have a modest effect on sleep or diurnal organization of sleep-wake cycles in mammals like rats (Meldenson and Bergmann, 2001; Fisher and Sugden, 2010). The exogenous administration of melatonin or its agonists is widely used as a treatment of insomnia, however, the question about mechanistic aspects of the involvement of exogenous melatonin in sleep promotion remains an open question. A recent study has reported that the administration of IIK7, an MT2 subtype selective agonist, has an acute sleep-promoting action in the rat, which is very similar to that seen after the administration of melatonin, suggesting that an MT2 melatonin receptor subtype mediates the acute hypnotic effect of melatonin (Fisher and Sugden, 2009)

Photoperiodic Responses
Physiological time measurement is linked to photoperiodism (Figure 3). The pineal gland via melatonin mediates photoperiodic time measurement in mammals (Malpaux et al., 2001; Hezlerigg 2010). Pinealectomy is reported to block photoperiodic responses in all experimental mammals studied so far (Hezlerigg and Wagner, 2006). In mammals, environmental light information is received by the classical retinal photoreceptors (rods and cones), or ipRGCs is conveyed via the SCN (Card et al., 1991; Lucas et al., 1999; Paul et al., 2009) to the pineal gland, which via melatonin regulates seasonal photoperiodic responses in many mammalian species (Bartness et al., 1993; Bittman and Karsch, 1984). Long duration melatonin signals promote winter physiology, while short duration signals promote summer physiology (Lincoln et al., 2005). The infusion of melatonin in pinealectomised mammals activated photoperiod dependent seasonal physiology (Bartness et al., 1993).

Figure 3. Light perceived through the retinal photoreceptors (PR), and transmitted through the retino-hypothalamic tract (RHT), affects mammalian reproduction via a complex pathway that involves the pineal, the suprachaismatic nucleus (SCN) of the hypothalamus (HYP), the paraventricular nuclei, (PVN), superior cervical ganglion (SCG), and the pituitary gland. Hormones secreted include gonadotropin releasing hormone (GnRH) from the hypothalamus, leutinizing hormone (LH), and follicle stimulating hormone (FSH) from the pituitary, which affects gonadal activity.

Exposure of Syrian hamsters to short day lengths (less than 12.5 hr of light) decreases the blood concentration of gonadotropins (FSH, LH) and sex steroids (progesterone, testosterone), which leads to gonadal regression (by 10%) followed by reproductive quiescence for about 16-20 weeks, which corresponds to the duration of autumn and winter (Prendergast et al., 2009). During this time of gonadal recrudescence the gonads become photorefractory (gonadal conditions are unlinked to photoperiodic inhibition), a condition that enables the gonads to become functional in spring before the environmental photoperiods return to 12.5 hr. Photorefractoriness can be terminated by the exposure of animals to long day lengths (Butler et al., 2010). To answer if melatonin is involved in this process, studies with microimplants of melatonin in the SCN and parts of the thalamus of photorefractory Siberian hamsters for 12 weeks during exposure to long daylengths were capable of blocking the dissipation of photorefractoriness by long daylengths (Teubner et al., 2008). However, a recent study by Butler et al., (2010) has shown that the seasonal transition to summer photosensitive phenotype, which is essential for reproduction in seasonal breeding mammals, is melatonin independent.

The nightly duration of melatonin secretion is reported to affect reproduction by altering the steroid negative feedback effects on the hypothalamus and pituitary. In humans, melatonin down regulates the expression of hypothalamic GnRH in a cyclic pattern over a 24 hr period, an effect mediated by its G-protein coupled MT1 and MT2 receptors. This influences the pulsatile secretion of gonadal steroids, namely follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary. A decline in melatonin concentration below the threshold level (115 pg/ml) is thus essential for the initiation of puberty (Juszczak and Michalska, 2006), while an early decline in melatonin concentration may activate the hypothalamo-gonadal axis, leading to precocious puberty in humans (Commentz and Helmke, 1995). The fact that young boys with pineal tumors show precocious puberty is indicative of the involvement of the pineal (Silman et al., 1979) and melatonin in this process (de Holanda et al., 2010). The molecular mechanism underlying the role of melatonin during puberty can be explained through recent investigations, which highlight the fact that members of the Rfamide family of peptides like kisspeptine and gonadotropin inhibiting hormone (GnIF), which have antogonastic effects on hypothalamic GnRH neurons (kisspeptin stimulating and GnIF inhibiting GnRH secretion), is influenced by melatonin (Smith and Clarke, 2007). Melatonin increases GnIF secretion and inhibits kisspeptin secretion in cultured mammalian hypothalamic neurons (Gingerich et al., 2009).

The direct MT1 and MT2 mediated effect of melatonin on human ovarian granulosa cells influences LH secretion and ovarian lutinization (Woo et al., 2001). Melatonin treatment increases human chorionic gonadotropin stimulated progesterone secretion by the corpus luteum through inhibition of ovarian GnRH (Stocco et al., 2007). Taken together, these studies indicate the involvement of pineal and melatonin in the regulation of reproduction in seasonally reproducing mammal, as well as in humans.

Melatonin and Glucose metabolism
New data have also suggested a role for melatonin in the regulation of carbohydrate metabolism (Peschke, 2008), and indeed, a recent study using melatonin receptor knock-out mice has indicated an active role of these receptors in the regulation of blood glucose (Muhlbauer et al., 2009). A recent paper has also reported that melatonin treatment can improve glucose metabolism in an insulin-resistant mouse model by restoring the action of insulin on the vasculature (Sartori et al., 2009). Additional support for a role of melatonin in the regulation of glucose metabolism has been provided by a series of studies that have linked melatonin receptor type 2 in the pathogenesis of type 2 diabetes (Bouatia-Naji et al., 2009; Lyssenko et al., 2009). Finally, a recent investigation has shown that the removal of MT1 induces insulin resistance in the mouse (Contreras-Alcantara et al., 2010). The mechanism by which melatonin affects glucose metabolism is still under investigation, but it is believed that melatonin may modulate insulin secretion by the pancreas, and glucose uptake by skeletal muscle.

Extensive studies over the last 50 years have shown that the pineal gland and melatonin play an important role in the modulation of many aspects of mammalian physiology. Although this article attempts to highlight the versatile role of pineal and melatonin in the regulation of mammalian physiology, in no way can it summarize the entire spectrum of physiological functions regulated by the pleiotropic hormone melatonin or pineal. Further studies are necessary for the full elucidation of the functional role of the mammalian pineal and its principle indole melatonin.


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