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Vol. 56, Issue 2, 279-289, August 1999

Inducible Cyclic AMP Early Repressor Protein in Rat Pinealocytes: A Highly Sensitive Natural Reporter for Regulated Gene Transcription

Martina Pfeffer, Erik Maronde, Carlos A. Molina, Horst-Werner Korf, and Jörg H. Stehle

Dr. Senckenbergische Anatomie, Institute for Anatomy II, Johann Wolfgang Goethe-University Frankfurt, Frankfurt, Germany (M.P., E.M., H.-W.K., J.H.S.); and Department of Obstetrics and Gynecology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey (C.A.M.)

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 cyclic AMP (cAMP)-signaling pathway, cAMP response element-binding protein and inducible cAMP early repressor (ICER), respectively. Activation of this pathway is centered around norepinephrine, stimulating beta 1-adrenergic receptors, but various other transmitters can modulate melatonin biosynthesis. To compare the transcriptional impact of norepinephrine with that of other neurotransmitters on melatonin synthesis, we determined ICER protein levels in pinealocytes and, in parallel, hormone secretion. The dose-dependent inductions of ICER protein by norepinephrine, the beta 1-adrenergic receptor agonist isoproterenol, vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide, and adenosine are correlated to regulatory dynamics in melatonin production. Importantly, ICER protein induction required lower ligand concentrations than the induction of melatonin biosynthesis. Although neuropeptide Y, glutamate, and vasopressin altered norepinephrine-stimulated hormone production without affecting ICER levels, the activation of voltage-gated cation channels increased ICER without affecting hormone synthesis. Sensitivity and versatility of ICER induction in pinealocytes make these neuroendocrine cells a valuable model system in which to study molecular interactions determining a regulated gene expression.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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