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

reductase 2 (QR2), an enzyme involve in detoxification in mouse

(11). QR2 seems to have antioxidants properties although is diffi-

cult to establish a clear role in detoxification on the basis of the

currently available experiments. Furthermore, many tissues deprived

of QR2 genes lack melatonin binding sites. These data indicate that

in many cases is indeed QR2 the MT3 melatonin receptor (12).
Nevertheless, there are other cases in which it has not been possible

to match the presence of QR2 and the putative MT3 melatonin
receptor (11). Moreover unexpectedly, the binding of melatonin and

derivatives to QR2 does not inhibit the activity of the enzyme when

the natural substrate is present (menadione), although it occupies

the enzyme active site (12). The notion that arises is that binding

approaches for melatonin and derivatives on the QR2/MT3 receptor
is not enough to discard the existence of a real receptor with a clear-

cut physiological action. Moreover, in both mammals and non-

mammals there is a correlation between the pharmacological profile

of the putative MT3 receptor and the generation of IP3 and
diacylglycerol (13). Nevertheless, it is necessary investigate the

possibility of cloning a different protein from QR2 that may match

with the putative MT3 receptor to fully dissipate this controversial
point.

Cloning the MT3 receptor

This is indeed one of our main tasks at the moment. Based on the
sequences of QR2, MT1 and MT2 receptors, we are trying to hunt the
putative MT3 receptor. We have started to dive in ocular tissues and
we have cloned a DNA sequence which presents the sequence of the
MT2 melatonin receptor but which has an insert of 90 pb suggesting
it is a new specie. It is clear that it can be either a splice variant or
the MT3 receptor. The insert is not only increasing the length of the
protein encoded by the gene but also is altering the reading frame
that probably will generate a different protein from the cloned MT2.
This interesting discovery is more significant because the ocular
tissue where it has been obtained, the cornea, lacks of the QR2 gene.
We need to conclude this research since either we have the MT3
receptor or we have a MT2 receptor (splicing variant) with a different
selectivity for melatonins, in particular for 5-MCA-NAT.

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