The pineal hormone, melatonin, is an important regulator of seasonal 
reproduction and circadian rhythms. Its effects are mediated via high-affinity 
melatonin receptors, located on cells of the pituitary pars tuberalis (PT) and 
suprachiasmatic nucleus (SCN), respectively. Two subtypes of mammalian melatonin 
receptors have been cloned and characterized, the MT1 (Mel(1a)) and the MT2 
(Mel(1b)) melatonin receptor subtypes. Both subtypes are members of the 
seven-transmembrane G protein-coupled receptor family. By using recombinant 
melatonin receptors it has been shown that the MT1 melatonin receptor is coupled 
to different G proteins that mediate adenylyl cyclase inhibition and 
phospholipase C beta activation. The MT2 receptor is also coupled to inhibition 
of adenylyl cyclase and additionally it inhibits the soluble guanylyl cyclase 
pathway. In mice with a targeted deletion of the MT1 receptor, the acute 
inhibitory effects of melatonin on SCN multiunit activity are completely 
abolished, while the phase-shifting responses to melatonin (given in 
physiological concentrations) appear normal. Furthermore, melatonin inhibits the 
phosphorylation of the transcription factor cyclic AMP response element binding 
protein, induced by the pituitary adenylate cyclase-activating polypeptide in 
SCN cells predominantly via the MT1 receptor. However, a functional MT2 receptor 
in the rodent SCN is partially able to compensate for the absence of the MT1 
receptor in MT1 receptor-deficient mice. These findings indicate redundant and 
non-redundant roles of the receptor subtypes in regulating SCN function. In the 
PT, a functional MT1 receptor is essential for the rhythmic synthesis of the 
clock gene product mPER1. Melatonin produces a long-lasting sensitization of 
adenylyl cyclase and thus amplifies cyclic AMP signaling when melatonin levels 
decline at dawn. This action of melatonin amplifies gene expression rhythms in 
the PT and provides a mechanism for reinforcing rhythmicity in peripheral 
tissues which themselves lack the capacity for self-sustained oscillation. Mice 
with targeted deletion of melatonin receptor subtypes provide an excellent model 
to understand cellular mechanisms through which melatonin modulates circadian 
and photoperiodic rhythmicity.