Elsevier

Life Sciences

Volume 72, Issue 20, 4 April 2003, Pages 2183-2198
Life Sciences

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Melatonin receptors and their regulation: biochemical and structural mechanisms

https://doi.org/10.1016/S0024-3205(03)00098-5Get rights and content

Abstract

There is growing evidence demonstrating the complexity of melatonin's role in modulating a diverse number of physiological processes. This complexity could be attributed to the fact that melatonin receptors belong to two distinct classes of proteins, that is, the G-protein coupled receptor superfamily (MT1, MT2) and the quinone reductase enzyme family (MT3) which makes them unique at the molecular level. Also, within the G-protein coupled receptor family of proteins, the MT1 and MT2 receptors can couple to multiple and distinct signal transduction cascades whose activation can lead to unique cellular responses. Also, throughout the 24-hour cycle, the receptors' sensitivity to specific cues fluctuates and this sensitivity can be modulated in a homologous fashion, that is, by melatonin itself, and in a heterologous manner, that is, by other cues including the photoperiod or estrogen. This sensitivity of response may reflect changes in melatonin receptor density that also occurs throughout the 24-hour light/dark cycle but out of phase with circulating melatonin levels. The mechanisms that underlie the changes in melatonin receptor density and function are still not well-understood, but data is beginning to show that transcriptional events and G-protein uncoupling may be involved. Even though this area of research is still in its infancy, great strides are being made everyday in elucidating the mechanisms that underlie melatonin receptor function and regulation. The focus of this review is to highlight some of these discoveries in an attempt to reveal the uniqueness of the melatonin receptor family while at the same time provide thought-provoking ideas to further advance this area of research. Thus, a brief overview of each of the mammalian melatonin receptor subtypes and the signal transduction cascades to which they couple will be discussed with a greater emphasis placed on the mechanisms underlying their regulation and the domains within the receptors essential for proper signaling.

Introduction

Melatonin, acting through melatonin receptors, is involved in numerous physiological processes including circadian entrainment [19], [42], [47], [72], [73], [82], blood pressure regulation [15], [79], oncogenesis [6], [62], [90], retinal physiology [18], seasonal reproduction [3], [52], [72], ovarian physiology [10], [40], and most recently in inducing osteoblast differentiation [69] (review by [41]). When one examines the diversity of response of one class of receptors, the question that comes to mind is: How can a single hormone produce such variable responses within the body? As one probes into the field of melatonin and its receptors, the answer to this important question becomes a little more obvious.

Many factors contribute to the diversity of the melatonin response within the body. First of all, melatonin levels fluctuate during the day and throughout the year [63]. For example, levels of melatonin are lowest during the day and highest at night and persist for longer periods of time during the winter months as compared to the summer months (Fig. 1). These fluctuations in melatonin levels in vivo can and do impact greatly on the functioning of the receptor. Melatonin can activate or inhibit signal transduction cascades independent of receptors or through receptors. The ability of melatonin to act independently from its receptors is attributed to its small and highly lipophilic nature and/or due to an active uptake mechanism [5], [21], [49]. There are multiple receptor subtypes available to which melatonin can bind and activate. Two of the melatonin receptor subtypes are G-protein coupled receptors [64], [65] while the third, which was recently affinity-purified, belongs to the family of quinone reductases [57]. Each of the G-protein coupled melatonin receptor subtypes, denoted MT1 and MT2, can couple to multiple signal transduction cascades whereas the signal transduction cascades mediating MT3 responses are still unclear. Finally, melatonin receptor expression and perhaps function can be regulated by multiple cues including the light/dark cycle, scheduled arousal, an endogenous pacemaker, by melatonin itself, and/or by other hormones.

The focus of this review is not to provide an exhaustive bibliography of melatonin receptors but rather strives to present data that highlights key areas of interest and debate in this area of research. Thus, a brief overview of each of the mammalian melatonin receptor subtypes and the signal transduction cascades to which they couple will be discussed with a greater emphasis placed on the mechanisms underlying their regulation and the domains within the receptors essential for proper signaling. For more comprehensive summaries of melatonin receptors, please refer to these other excellent reviews [45], [80], [83].

Section snippets

Melatonin Receptor Subtypes, Tissue Localization and Their Role in Physiological Processes

To date, three mammalian melatonin receptors have been either cloned, MT1 [64] MT2 [65] or affinity-purified, MT3 [57]. Two of these receptors are G-protein coupled receptors and are denoted as MT1 and MT2whereas the newly purified MT3 protein belongs to the family of the quinone reductases. The MT1 and MT2 melatonin receptors are classified as unique subtypes based on their molecular structure and chromosomal localization [65], [75], [76].

The amino acids involved in melatonin receptor activation and signaling

Melatonin receptors MT1 and MT2 are G-protein coupled receptors (GPCRs) that possess structural motifs consisting of seven membrane spanning domains connected by a series of extracellular and intracellular loops. The ability of melatonin to bind to, activate, and modulate its own receptors depends on the interaction of melatonin with specific amino acids and/or domains. This interaction may be with amino acids or domains unique to each receptor (i.e., MT1R- or MT2R-specific) or similar between

Regulation of Melatonin Receptors

Melatonin is released from the pineal gland in a circadian manner where melatonin levels peak at night and persist for about 8 hours. During the day, melatonin levels decrease by 10-fold and persist for about 16 hours [63]. Because melatonin receptors are exposed daily to melatonin for prolonged periods of time, desensitization is thought to be an essential component underlying the functional effects of melatonin within the body. Prolonged exposure of MT1R to melatonin results in the

G-protein Uncoupling

As shown in both in vitro and in vivo models, changes in the coupling of melatonin receptors to G-proteins can dramatically dictate how well melatonin can bind to and activate its receptor [22], [23], [78], [87]. The mechanisms underlying changes in melatonin receptor/G-protein coupling are still not well understood, but progress is being made. For example, in CHO cells expressing the MT1R and following melatonin exposure, increases in the heterotrimeric, undissociated form (Giαβγ) of Gi

Heterologous Regulation of Melatonin Receptors

Besides melatonin, the photoperiod may play an important role in regulating melatonin receptor density. For example, in the rat suprachiasmatic nucleus (SCN) of the hypothalamus that is the master biological clock, the density of melatonin receptors varies with the light/dark cycle. Levels of receptor are lower during the night when compared to levels during the day. This fluctuation in receptor density occurs even in pinealectomized rats [47] suggesting the involvement of the light/dark cycle.

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