Inhibition by antidepressant drugs of cyclic AMP response element-binding protein/cyclic AMP response element-directed gene transcription

Abstract

Clinical observations agree that antidepressant drugs are effective only after a lag phase of 1-3 weeks. This delay could be explained at the molecular level by an action on gene transcription. Transcription of many genes is directed by the cAMP/Ca(2+)-responsive element (CRE) and its cognate transcription factor CRE-binding protein (CREB). Membrane depolarization and cAMP induce the phosphorylation of CREB at Ser-119 and thereby stimulate the transcriptional activity of CREB. The effect of antidepressant drugs on CREB/CRE-directed gene transcription was investigated using transient transfections of reporter fusion genes in HIT and PC-12 cells. Clomipramine, imipramine, fluoxetine, doxepin, desipramine, amitriptyline, maprotiline, mianserin, and trazodone inhibited CRE-directed gene transcription that was stimulated by membrane depolarization, with IC50 values between 70 nM and 1.73 microM. Desipramine had no effect on transcription after stimulation by cAMP but blocked the synergistic effect of cAMP and membrane depolarization to the level of stimulation by cAMP alone. Upon membrane depolarization, desipramine reduced the phosphorylation of CREB at Ser-119 and also blocked the depolarization-induced increase in the intracellular free Ca2+ concentration in HIT cells. Thus, by interfering with the depolarization-induced activation of the transcription factor CREB, antidepressant drugs can inhibit CRE-directed gene transcription, which could underlie the pharmacological effects of these clinically important drugs.