Genomic Regulation of the PACAP Receptor, PAC1, and Implications for Psychiatric Disease

Impairment of the hypothalamic-pituitary-adrenal (HPA) axis and related neurological signaling has been attributed to several psychiatric conditions including unipolar and bipolar depression and posttraumatic stress disorder (PTSD). Consequently, irregularities in the mRNA expression or protein levels of neuropeptide hormones and receptors involved in related stress pathways can trigger these neurological disorders. As a critical modulator of the stress and fear pathways in concert with the pituitary adenylate cyclase-activating peptide (PACAP) ligand, the PAC1 receptor (PAC1) has been implicated in risk for PTSD. Genetic variants, epigenetic alterations, and hormone regulation have been attributed to changes in the expression of ADCYAP1R1 which encodes the PAC1 protein. The chapter will focus on a review of PACAP-induced cellular function, localization, and expression of the PAC1 receptor. The goal of this review is to address the effects of altered expression of PAC1 on phenotypic outcomes, particularly those neurological in nature. We also discuss existing and potential mechanisms that can induce changes in ADCYAP1R1 transcript levels, including genetic and epigenetic alterations and hormone regulation.