AP1 PROTEINS MEDIATE THE CAMP RESPONSE OF THE DOPAMINE-BETA-HYDROXYLASE GENE

Neurotransmitter biosynthesis is regulated by environmental stimuli, w hich transmit intracellular signals via second messengers and protein kinase pathways, For the catecholamine biosynthetic enzymes, dopamine beta-hydroxylase and tyrosine hydroxylase, regulation of gene expressi on by cyclic AMP, diacyl glycerol, and Ca2+ leads to increased neurotr ansmitter biosynthesis, In this report, we demonstrate that the cAMP-m ediated regulation of transcription from the dopamine beta-hydroxylase promoter is mediated by the AP1 proteins c-Fos, c-Jun, and JunD, Foll owing treatment of cultured cells with cAMP, protein complexes bound t o the dopamine beta-hydroxylase AP1/cAMP response element element chan ge from consisting of c-Jun and JunD to include c-Fos, c-Jun, and JunD . The homeodomain protein Arix is also a component of this DNA-protein complex, binding to the adjacent homeodomain recognition sites. Trans fection of a dominant negative JunD expression plasmid inhibits cAMP-m ediated expression of the dopamine beta-hydroxylase promoter construct in PC12 and CATH.a cells. In addition to the role of c-Fos in regulat ing dopamine beta-hydroxylase gene expression in response to cAMP, a s econd pathway, involving Rap1/BRaf is involved. These experiments illu strate an unusual divergence of cAMP-dependent protein kinase signalin g through multiple pathways that then reconverge on a single element i n the dopamine beta-hydroxylase promoter to elicit activation of gene expression.