Down-regulation of protein kinase A occurs by a feedback mechanism: one of the substrates that is activated by the kinase is a phosphodiestrase, which converts cAMP to AMP, thus reducing the amount of cAMP that can activate protein kinase A. In the nucleus, PKA modulates the activity of various cAMP-responsive - factors (e.g. CREB), which regulate the transcription of important genes like the gene encoding for the brain-derived neurotrophic factor, which has been demonstrated to be involved both in depression and suicide. The gene discussed is CREB1; the disease is major depressive disorder.