Inducible cyclic AMP early repressor protein in rat pinealocytes: A highlysensitive natural reporter for regulated gene transcription

Rhythmic activity of arylalkylamine N-acetyltransferase (AANAT) determines melatonin synthesis in rat pineal gland. The transcriptional regulation of AANAT involves the activating and inhibiting transcription factors of the c yclic AMP (cAMP)signaling pathway, cAMP response element-binding protein an d inducible cAMP early repressor (ICER), respectively. Activation of this p athway is centered around norepinephrine, stimulating beta(1)-adrenergic re ceptors, but various other transmitters can modulate melatonin biosynthesis . To compare the transcriptional impact of norepinephrine with that of othe r neurotransmitters on melatonin synthesis, we determined ICER protein leve ls in pinealocytes and, in parallel, hormone secretion. The dose-dependent inductions of ICER protein by norepinephrine, the beta(1)-adrenergic recept or agonist isoproterenol, vasoactive intestinal peptide, pituitary adenylat e cyclase-activating polypeptide, and adenosine are correlated to regulator y dynamics in melatonin production. Importantly, ICER protein induction req uired lower ligand concentrations than the induction of melatonin biosynthe sis. Although neuropeptide Y, glutamate, and vasopressin altered norepineph rine-stimulated hormone production without affecting ICER levels, the activ ation of voltage-gated cation channels increased ICER without affecting hor mone synthesis. Sensitivity and versatility of ICER induction in pinealocyt es make these neuroendocrine cells a valuable model system in which to stud y molecular interactions determining a regulated gene expression.