Of rodents and ungulates and melatonin: Creating a uniform code for darkness by different signaling mechanisms

Melatonin synthesis in the mammalian pineal gland is one of the best invest igated output pathways of the circadian clock because it can be readily mea sured and is tightly regulated by a clearly defined input, the neurotransmi tter norepinephrine. In this system, a regulatory scenario was deciphered t hat is centered around the cyclic AMP pathway but shows peculiar species-sp ecific differences. In rodents, the cyclic AMP-mediated, temporally sequent ial up-regulation of two transcription factors, the activator CREB (cyclic AMP-responsive element-binding protein) and the inhibitor ICER (inducible c yclic AMP-dependent early repressor), is the core mechanism to determine rh ythmic accumulation of the mRNA encoding for the rate-limiting enzyme in me latonin synthesis, the arylalkylamine N-acetyltransferase (AA-NAT). Thus, i n rodents, the regulation of melatonin synthesis bears an essential transcr iptional component, which, however, is flanked by posttranscriptional mecha nisms. In contrast, in ungulates, and possibly also in primates, AA-NAT app ears to be regulated exclusively on the posttranscriptional level. Here, in creasing cyclic AMP levels inhibit the breakdown of constitutively synthesi zed AA-NAT protein by proteasomal proteolysis, leading to an elevated enzym e activity. Thus, self-restriction of cellular responses, as a reaction to external cues, is accomplished by different mechanisms in pinealocytes of d ifferent mammalian species. In such a temporally gated cellular adaptation, transcriptionally active products of clock genes may play a supplementary role. Their recent detection in the endogenously oscillating nonmammalian p ineal organ and, notably, also in the slave oscillator of the mammalian pin eal gland underlines that the mammalian pineal gland will continue to serve as an excellent model system to understand mechanisms of biological timing .