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Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor
Open accessAbstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. In contrast, it is unclear if the PACAP-PAC1 receptor pathway has a role in human psychological stress responses, such as post-traumatic stress disorder (PTSD). Here we find, in heavily traumatized subjects, a sex-specific association of PACAP blood levels with fear physiology, PTSD diagnosis and symptoms in females. We examined 44 single nucleotide polymorphisms (SNPs) spanning the PACAP (encoded by ADCYAP1) and PAC1 (encoded by ADCYAP1R1) genes, demonstrating a sex-specific association with PTSD. A single SNP in a putative oestrogen response element within ADCYAP1R1, rs2267735, predicts PTSD diagnosis and symptoms in females only. This SNP also associates with fear discrimination and with ADCYAP1R1 messenger RNA expression in human brain. Methylation of ADCYAP1R1 in peripheral blood is also associated with PTSD. Complementing these human data, ADCYAP1R1 mRNA is induced with fear conditioning or oestrogen replacement in rodent models. These data suggest that perturbations in the PACAP-PAC1 pathway are involved in abnormal stress responses underlying PTSD. These sex-specific effects may occur via oestrogen regulation of ADCYAP1R1. PACAP levels and ADCYAP1R1 SNPs may serve as useful biomarkers to further our mechanistic understanding of PTSD.
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“It seems that pituitary adenylate-cyclase activating peptide/pituitary adenylate-cyclase 1 pathway exhibits a role in psychological stress response, which is dependent on an estrogen response element that conveys sex specific-modulation of fear response.”
From Oxidative Stress Implications in the Affective Disorders: Main Biomarkers, Animal Models Relevance, Genetic Perspectives, and Antioxidant Approaches (2016) · cites this paper as [197]
In the citing paper
“In addition, the female predisposition to PTSD may be modulated by a recently found single nucleotide polymorphism of estrogen response element, found on pituitary adenylate-cyclase 1 receptor gene [197].”
From Oxidative Stress Implications in the Affective Disorders: Main Biomarkers, Animal Models Relevance, Genetic Perspectives, and Antioxidant Approaches (2016) · cites this paper as [197]
In the citing paper
“For example, a polymorphism in the pituitary adenylate cyclase-activating polypeptide receptor gene (ADCYAP1R1) is associated with decreased fear discrimination in females but not males (95).”
From Conditioned fear associated phenotypes as robust, translational indices of trauma-, stressor-, and anxiety-related behaviors (2014) · cites this paper as [95]
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Cites
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Self-citationDifferential signal transduction by five splice variants of the PACAP receptor
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Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery
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Biological studies of post-traumatic stress disorder
Pitman, R. K., Rasmusson, A. M., Koenen, K. C., Shin, L. M., Orr, S. P., Gilbertson, M. W., Milad, M. R., & Liberzon, I. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3339 · Cited by 1,529
Fear Extinction as a Model for Translational Neuroscience: Ten Years of Progress
Milad, M. R., & Quirk, G. J. (2012) · Annual Review of Psychology · doi:10.1146/annurev.psych.121208.131631 · Cited by 1,466
Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions
Klengel, T., Mehta, D., Anacker, C., Rex-Haffner, M., Pruessner, J. C., Pariante, C. M., Pace, T. W. W., Mercer, K. B., Mayberg, H. S., Bradley, B., et al. (2013) · Nature Neuroscience · doi:10.1038/nn.3275 · Cited by 1,447
Self-citationSex differences in anxiety and depression clinical perspectives
Altemus, M., Sarvaiya, N., & Neill Epperson, C. (2014) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2014.05.004 · Cited by 1,413
“In addition, blood levels of PACAP, a neuropeptide involved in coordinating the brain’s response to stress and a polymorphism in the gene that encodes PACAP’s receptor PAC1, are both associated with increased risk for PTSD in women, but not in men (Ressler et al., 2011).”
BackgroundRusso, S. J., Murrough, J. W., Han, M.-H., Charney, D. S., & Nestler, E. J. (2012) · Nature Neuroscience · doi:10.1038/nn.3234 · Cited by 1,206
Metadata
- Authors
- Ressler, K. J., Mercer, K. B., Bradley, B., Jovanovic, T., Mahan, A., Kerley, K., Norrholm, S. D., Kilaru, V., Smith, A. K., Myers, A. J., Ramirez, M., Engel, A., Hammack, S. E., Toufexis, D., Braas, K. M., Binder, E. B., & May, V.
- Affiliations
- Howard Hughes Medical Institute (US)
- Emory University (US)
- Emory National Primate Research Center (US)
- University of Miami (US)
- University of Vermont (US)
- Corresponding author
- Ressler, Kerry J.
- ORCID
- Venue
- Nature
- Published
- 2011-02-23
- Volume
- 470
- Issue
- 7335
- Pages
- 492-497
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3046811
- OpenAlex
- W2068480672
- Cited by
- 800
- References
- 42
- Citations by year
- 2026: 27 · 2025: 31 · 2024: 35 · 2023: 39 · 2022: 45 · 2021: 66 · 2020: 53 · 2019: 42 · 2018: 55 · 2017: 57 · 2016: 76 · 2015: 57 · 2014: 63 · 2013: 64 · 2012: 58
- FWCI
- 74.73
- Type
- journal article
- Language
- en
- Update notices
- addendum (2011-08-31)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (UL1TR000454)
- National Institute on Aging (AG-034504, R01AG034504)
- National Institute of Mental Health (MH 071537, R01MH071537, R56MH071537)
- National Institute on Drug Abuse (R01DA019624, DA-019624)
- National Center for Research Resources (M01-RR00039, P20-RR16435, P20RR016435, M01RR000039)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-27468, R01HD027468)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- post-traumatic stress disorder, PACAP, PAC1 receptor, ADCYAP1, ADCYAP1R1, sex differences, fear conditioning, estrogen response element, single nucleotide polymorphisms, DNA methylation, biomarkers, amygdala, stress response, estrogen replacement therapy
- MeSH terms
- Amygdala, Animals, Conditioning, Classical, Estrogens, Fear, Female, Gene Expression Regulation, Humans, Male, RNA, Messenger, Septal Nuclei, Sex Characteristics, Stress Disorders, Post-Traumatic, CpG Islands, DNA Methylation, Genetic Predisposition to Disease, Response Elements, Polymorphism, Single Nucleotide, Pituitary Adenylate Cyclase-Activating Polypeptide, Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I, Mice, Rats, Genetic Association Studies
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