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Vol. 56, Issue 5, 1014-1024, November 1999
Institute of Pharmacology, University of Vienna, Vienna, Austria
(F.R., M.W., M.F., C.N.), and Institut Cochin de Genétique
Moléculaire, Paris, France (L.B., A.D.S., R.J.)
If stably expressed in human embryonic kidney (HEK)293 cells, the human
Mel1a-melatonin receptor activates
Gi-dependent, pertussis toxin-sensitive signaling pathways,
i.e., inhibition of adenylyl cyclase and stimulation of phospholipase
C
; the latter on condition that Gq is coactivated. The
antagonist luzindole blocks the effects of melatonin and acts as an
inverse agonist at the Mel1a receptor in both intact cells
and isolated membranes. This suggests that the Mel1a
receptor is endowed with constitutive activity, a finding confirmed on
reconstitution of the Mel1a receptor with Gi.
Because the receptor density is in the physiological range,
constitutive activity is not an artifact arising from overexpression of
the receptor. In addition, the following findings indicate that the Mel1a receptor forms a very tight complex with
Gi which can be observed both in the presence and absence
of an agonist. 1) In intact cells and in membranes, high-affinity
agonist binding is resistant to the destabilizing effect of guanine
nucleotides. 2) The ability to bind an agonist with high affinity is
preserved even after exposure of the cells to pertussis toxin, because
a fraction of Gi is inaccessible to the toxin in cells
expressing Mel1a receptors (but not the
A1-adenosine receptor, another Gi-coupled receptor). 3) An antiserum directed against the Mel1a
receptor coprecipitates Gi even in the absence of an
agonist. We therefore conclude that the Mel1a receptor is
tightly precoupled and that its constitutive activity may play a role
in pacing the biological clock, an action known to involve the
melatonin receptors in the suprachiasmatic nucleus.
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