Pineal gene expression: dawn in a dark matter

The mammalian pineal gland serves as a neuroendocrine interface to convert environmental lighting conditions into a humoral message, the nocturnally elevated synthesis of melatonin. Regulation and fine tuning of the circadian melatonin production in response to external cues requires complex interactions of transsynaptic signalling. These requirements are fulfilled by a high degree of plasticity on all levels between receptor activation and cellular response. Many receptors on pinealocytic membranes and enzymes involved in melatonin synthesis are linked to the second messenger cAMP. Crosstalk between second and third messengers converges in the pineal gland--as in other tissues--eventually on a modulated activity of transcription factors. Of fundamental importance for genes involved in the transsynaptic signalling to create a circadian profile in melatonin synthesis is the cAMP-inducible promoter element, the CRE (cAMP responsive element). Indeed, the CRE is shared by many pineal genes that are of physiological importance. Recently, the deciphering of molecular determinants regulating expression of cAMP-inducible genes in the mammalian pineal gland, like NAT, c-jun, or the beta-adrenergic receptor suggests a modulation in their transcription by a dual regulatory mechanism: posttranslational activation of the early third messenger CREB (cAMP responsive element binding protein) stimulates, cis-acting cAMP-induced transcriptional upregulation of the late third messenger ICER (inducible cAMP early repressor) inhibits genes with a CRE.