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VOL. 73 (4), 947-962, 2007 MELATONIN MAKES ME FEEL AWAKE!...

receptor is defined as a high-affinity (picomolar) site and a ML2 as
a low-affinity, (nanomolar) site (15). Originally, the nomenclature
ML1 / ML2 was the one used for both mammals and non-mammals
before the receptors were cloned. It is currently used in non-
mammalian experimental models, for that reason we consider of
interest to illustrate them.

ML1 includes the non-mammalian melatonin receptor isoforms
Mel1a, Mel1b and Mel1c. The Mel1a receptor sequence is
homologous to the mammalian MT1 receptor while the Mel1b is
equivalent to the mammalian MT2 receptor. There is another subtype
without a corresponding orthologue in mammals termed Mel1c.

Mammalian melatonin receptors types MT1 and MT2 belong to
class A rhodopsin-like GPCRs and present seven transmembrane
hydrophobic helices. MT1 and MT2 melatonin receptors are formed
from 350 and 362 aminoacids, respectively, with molecular weights
of 39-40 kDa (19). These two melatonin receptors are encoded by
genes located in different chromosomes (20). The gene for the MT1
receptor is located in position 4q35-1 (21) and the gene for the MT2
receptor in 11q21-22 (20). Both share approximately 60% homology
with each another (17). The existence of three extracellular loops
alternating with three intracellular loops to link the seven
transmembrane regions, indicate the presence of potential sites for
phosphorylation and glycosylation. The MT1 melatonin receptor has
two potential glycosylation sites in the N-terminal region (19), and
it may exist in more than one glycosylated form (17), while MT2 has
one potential glycosylation site in the N-terminal region (17, 19).

The signal transduction system associated to the activation of
MT1 or MT2 in target cells results in the inhibition of adenylate
cyclase activity (Figure 6) (22). Activation of these receptors inhibits
forskolin-induced cAMP formation with a subsequent decrease in
activated protein kinase A (23). This is the common rule in the
biochemical pathways for these two receptors, but it is not the only
mechanism in signal transduction they can trigger. Depending on
the location, organ and species, melatonin by acting on the same
receptor can activate different second messenger cascades. This fact
provides a rich variability of mechanism that are probably related to
the physiological processes that are biochemically modulated.

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