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.
KeywordsEpigenetics Gene expression Genetic variants DNA methylation Splice isoforms Estradiol
Research in the Ressler Lab is supported by the Howard Hughes Medical Institute, NIH (R01MH096764), and by an NIH/NCRR base grant (P51RR000165) to the Yerkes National Primate Research Center.
Potential Conflict of Interest
Dr. Ressler is a founding member of Extinction Pharmaceuticals which exists to develop D-cycloserine for use to augment the effectiveness of psychotherapy. He has patents pending for the use of D-cycloserine and psychotherapy, targeting PACAP for extinction, targeting tachykinin 2 for prevention of fear, and targeting angiotensin to improve extinction of fear. He has received no equity or income from any of these relationships within the last 3 years. He has received funding from NIH, HHMI, NARSAD, and the Burroughs Wellcome Foundation.
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