ADCYAP1R1, also known as pituitary adenylate cyclase-activating polypeptide receptor 1, is associated with the hypothalamic-pituitary-adrenal (HPA) axis, which controls stress responses. It may be involved in the regulation of cAMP production as part of pathways like VIP-ADCYAP1R1-GNAS [3]. It has significance in biological processes related to stress response and is potentially involved in various diseases.

Multiple studies have explored its role in post-traumatic stress disorder (PTSD). A meta-analysis indicated that the C allele of rs2267735 in ADCYAP1R1 conferred significant risk for PTSD in combined-sex data and in female subsamples, but not in male subsamples [1]. Another study in a traumatized Chinese population found no significant main or gene-environment effects, but significant gene-gene interactions (ADCYAP1R1-FKBP5 and ADCYAP1R1-CRHR1) related to PTSD severity [2]. In female mice, acute stress immobilization led to fear extinction impairments related to Adcyap1r1 mRNA upregulation in the hypothalamus, and women with the risk genotype of ADCYAP1R1 rs2267735 polymorphism also had impaired fear extinction [4]. In pre-adolescent children, the ADCYAP1R1 CC genotype was associated with PTSD in girls but attenuated risk in boys [5]. In a pediatric population, the CC genotype of rs2267735 was associated with increased fear-potentiated startle over time, especially in females and those with high violence exposure [6]. Additionally, in Puerto Rican children, epigenetic and genetic variants in ADCYAP1R1 were associated with asthma [7], and in adult women, the "C" allele of ADCYAP1R1 rs2267735 interacted with childhood maltreatment to enhance the risk of PTSD [8].

In conclusion, ADCYAP1R1 plays a role in the stress response system, with its genetic variation influencing the risk of PTSD, especially in a sex-specific manner, and also being associated with asthma in children. Studies using genetic models in humans, though not traditional KO/CKO mouse models, have provided insights into how ADCYAP1R1 genetic variants interact with stress-related factors to impact disease risk in these areas.

References:

1. Lind, Mackenzie J, Marraccini, Marisa E, Sheerin, Christina M, Amstadter, Ananda B, Nugent, Nicole R. 2017. Association of Posttraumatic Stress Disorder With rs2267735 in the ADCYAP1R1 Gene: A Meta-Analysis. In Journal of traumatic stress, 30, 389-398. doi:10.1002/jts.22211. https://pubmed.ncbi.nlm.nih.gov/28746747/

2. Wang, Li, Zhang, Jingyi, Li, Gen, Zhang, Yingqian, Zhang, Kunlin. 2021. The ADCYAP1R1 Gene Is Correlated With Posttraumatic Stress Disorder Symptoms Through Diverse Epistases in a Traumatized Chinese Population. In Frontiers in psychiatry, 12, 665599. doi:10.3389/fpsyt.2021.665599. https://pubmed.ncbi.nlm.nih.gov/34163384/

3. Li, Chuanhao, Shen, Wenyuan, Xu, Zhengyu, Wang, Zhishuo, Feng, Shiqing. 2023. The discovery of the new mechanism: Celastrol improves spinal cord injury by increasing cAMP through VIP-ADCYAP1R1-GNAS pathway. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 165, 115250. doi:10.1016/j.biopha.2023.115250. https://pubmed.ncbi.nlm.nih.gov/37531781/

4. Velasco, E R, Florido, A, Flores, Á, Jovanovic, T, Andero, R. 2022. PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus. In Nature communications, 13, 4374. doi:10.1038/s41467-022-31442-w. https://pubmed.ncbi.nlm.nih.gov/35902577/

5. Danzi, BreAnne A, La Greca, Annette M. 2023. Does age matter in genetics? The role of ADCYAP1R1 in sex-specific risk for posttraumatic stress disorder in trauma-exposed preadolescent children. In Journal of psychiatric research, 164, 291-295. doi:10.1016/j.jpsychires.2023.06.024. https://pubmed.ncbi.nlm.nih.gov/37392718/

6. Jovanovic, Tanja, Stenson, Anaïs F, Thompson, Nadia, Bradley, Bekh, Ressler, Kerry J. 2020. Impact of ADCYAP1R1 genotype on longitudinal fear conditioning in children: interaction with trauma and sex. In Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 45, 1603-1608. doi:10.1038/s41386-020-0748-2. https://pubmed.ncbi.nlm.nih.gov/32590837/

7. Chen, Wei, Boutaoui, Nadia, Brehm, John M, Canino, Glorisa, Celedón, Juan C. 2013. ADCYAP1R1 and asthma in Puerto Rican children. In American journal of respiratory and critical care medicine, 187, 584-8. doi:10.1164/rccm.201210-1789OC. https://pubmed.ncbi.nlm.nih.gov/23328528/

8. Uddin, Monica, Chang, Shun-Chiao, Zhang, Chao, Aiello, Allison E, Koenen, Karestan C. 2012. Adcyap1r1 genotype, posttraumatic stress disorder, and depression among women exposed to childhood maltreatment. In Depression and anxiety, 30, 251-8. doi:10.1002/da.22037. https://pubmed.ncbi.nlm.nih.gov/23280952/