Publication Date:
2011-02-26
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046811/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046811/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ressler, Kerry J -- Mercer, Kristina B -- Bradley, Bekh -- Jovanovic, Tanja -- Mahan, Amy -- Kerley, Kimberly -- Norrholm, Seth D -- Kilaru, Varun -- Smith, Alicia K -- Myers, Amanda J -- Ramirez, Manuel -- Engel, Anzhelika -- Hammack, Sayamwong E -- Toufexis, Donna -- Braas, Karen M -- Binder, Elisabeth B -- May, Victor -- AG034504/AG/NIA NIH HHS/ -- DA019624/DA/NIDA NIH HHS/ -- HD27468/HD/NICHD NIH HHS/ -- M01RR00039/RR/NCRR NIH HHS/ -- MH071537/MH/NIMH NIH HHS/ -- P20RR16435/RR/NCRR NIH HHS/ -- R01 AG034504/AG/NIA NIH HHS/ -- R01 HD027468/HD/NICHD NIH HHS/ -- R01 HD027468-13/HD/NICHD NIH HHS/ -- UL1 TR000454/TR/NCATS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Feb 24;470(7335):492-7. doi: 10.1038/nature09856.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA. kressle@emory.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21350482" target="_blank"〉PubMed〈/a〉
Keywords:
Amygdala/metabolism
;
Animals
;
Conditioning, Classical/physiology
;
CpG Islands/genetics
;
DNA Methylation
;
Estrogens/metabolism/pharmacology
;
Fear/physiology
;
Female
;
Gene Expression Regulation/drug effects
;
Genetic Association Studies
;
Genetic Predisposition to Disease/*genetics
;
Humans
;
Male
;
Mice
;
Pituitary Adenylate Cyclase-Activating Polypeptide/*blood/chemistry
;
Polymorphism, Single Nucleotide/genetics
;
RNA, Messenger/analysis/biosynthesis/genetics
;
Rats
;
Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I/*genetics
;
Response Elements/genetics
;
Septal Nuclei/drug effects/metabolism
;
Sex Characteristics
;
Stress Disorders, Post-Traumatic/*blood/*genetics/physiopathology/psychology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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