Original Article
Melatonin receptors: Role on sleep and circadian rhythm regulation
Margarita L. Dubocovich
*
Department of Molecular Pharmacology and Biological Chemistry, Department of Psychiatry and Behavioral Science,
Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Abstract
The circadian release of the hormone melatonin is regulated by the suprachiasmatic nucleus (SCN), which feeds back into the
nucleus to modulate sleep and circadian phase through activation of the MT
1
and/or MT
2
melatonin receptors. Considering the
functions of the SCN as a sleep and circadian rhythm regulator, melatonin and melatonin receptor agonists have attracted interest
as being possible treatments for sleep and circadian rhythm sleep disorders. Part of this interest has centered on elucidating which
melatonin receptors are targets for the regulation of these functions within the SCN. Two G-protein coupled melatonin receptors,
the MT
1
and MT
2
, inhibit neuronal activity and phase shift circadian firing rhythms in the SCN, respectively. Recent reports have
uncovered possible interactions between the two types of receptors in the mammalian SCN, as well as the role of physiological and
supraphysiological levels of melatonin on the molecular pharmacology and cellular changes of human and rodent melatonin recep-
tors via desensitization and internalization mechanisms. These data outline the complexity of the interplay between melatonin and
its receptors in the SCN and their corresponding roles in sleep and circadian regulation. Although further studies are necessary, a
great deal of progress has been made toward understanding how melatonin and its agonists contribute to sleep and circadian phase
changes, and how best to develop compounds that can target the functions of the SCN specifically and effectively.
Ó 2007 Elsevier B.V. All rights reserved.
Keywords: MT
1
and MT
2
receptors; Phase shift; Inhibition of neuronal firing; Suprachiasmatic nucleus
1. Introduction
The suprachiasmatic nucleus (SCN), referred to as
the master circadian pacemaker, maintains the 24-h
cycle that regulates many biological functions ranging
from sleep to immune function [1,2]. The hormone mel-
atonin (5-methoxy-N-acetyltryptamine), primarily pro-
duced in the pineal gland and released during the
hours of darkness or subjective night, has significant
and important regulatory effects on the SCN. Melatonin
has been classically known to transduce photoperiodic
information, defining the length of the night [3–5]. The
SCN expresses at least two high-affinity melatonin
receptors, MT
1
and MT
2
[1,6]. These G-protein coupled
receptors, which show distinct molecular structures,
chromosomal localization, and pharmacological charac-
teristics, are co-localized within the SCN [1,6,7]. The
MT
1
and MT
2
melatonin receptors also show differen-
tial affinity for certain ligands, allowing the use of these
ligands to functionally characterize melatonin receptors
in native tissues [7] (Fig. 1).
MT
1
and MT
2
melatonin receptors are linked to acti-
vation of multiple signaling pathways, with inhibition of
cAMP formation through pertussis toxin sensitive
G-proteins being the most common [1]. In the mouse
SCN melatonin inhibits pituitary adenylate cyclase acti-
vating polypeptide (PACAP)-mediated CREB phos-
phorylation [8]. This effect appears to be mediated
primarily through activation of MT
1
receptors, as this
response is almost completely absent in MT
1
KO
(knockout) mice [8,9]. However, activation of the MT
2
melatonin receptor in the rat SCN appears to phase shift
1389-9457/$ - see front matter Ó 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.sleep.2007.10.007
*
Tel.: +1 312 503 8005; fax: +1 312 503 2334.
E-mail address: mdubo@northwestern.edu
www.elsevier.com/locate/sleep
Sleep Medicine 8 (2007) S34–S42