# ADCYAP1

## Overview
ADCYAP1 is a gene that encodes the pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide with significant roles in the central and peripheral nervous systems. PACAP is categorized as a neuropeptide and functions primarily through its interaction with G-protein coupled receptors, including PAC1, VPAC1, and VPAC2, to activate adenylate cyclase and elevate cyclic AMP (cAMP) levels. This signaling pathway is crucial for various physiological processes, such as neuroprotection, neurotransmission, and the regulation of circadian rhythms (Maugeri2020Effects; Baskozos2020Molecular). The gene's expression is widespread, encompassing the nervous system and peripheral organs, where it influences neuronal development, differentiation, and survival. ADCYAP1's involvement in neuroimmune interactions and its potential implications in neuropsychiatric disorders and cancer highlight its multifaceted biological significance (Ilanges2022Brainstem; hassan2017human).

## Function
The ADCYAP1 gene encodes the pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide involved in various molecular processes. PACAP functions by activating G-protein coupled receptors, specifically the PAC1 receptor and VPAC1/VPAC2 receptors, leading to the activation of adenylate cyclase and an increase in cyclic AMP (cAMP) levels. This signaling cascade influences numerous cellular processes, including neuroprotection, neurotransmission, and regulation of circadian rhythms (Maugeri2020Effects; Baskozos2020Molecular).

In healthy human cells, PACAP is expressed in both the central and peripheral nervous systems, as well as in peripheral organs such as the cardiovascular and respiratory systems, thyroid, and adrenal glands. It plays a crucial role in neuronal development, differentiation, and survival, facilitating neurite outgrowth and nerve regeneration. PACAP is also involved in growth cone guidance and cell survival in neurodegenerative conditions (Maugeri2020Effects; Schmid2019Molecular; Baskozos2020Molecular).

PACAP's expression in human skin and its interaction with sensory neurons suggest a role in sensory nerve function and regeneration. It is associated with the recovery of intraepidermal nerve fibers, indicating its potential therapeutic role in promoting nerve regeneration (Schmid2019Molecular; Baskozos2020Molecular).

## Clinical Significance
Alterations in the ADCYAP1 gene, which encodes the pituitary adenylate cyclase-activating polypeptide (PACAP), have been implicated in several neuropsychiatric and oncological conditions. In the context of schizophrenia, ADCYAP1 is considered a top risk gene, with its dysfunction potentially contributing to the disease's pathogenesis. Studies have shown that PACAP signaling, mediated through its receptor PAC1, is crucial for neural development and function, and deficiencies in this pathway can result in schizophrenia-like phenotypes in animal models (Mansouri2017PACAP; Matsuzaki2008Regulation). Genetic variants of ADCYAP1 have been associated with reduced hippocampal volume and poorer memory performance in schizophrenia patients (Matsuzaki2008Regulation).

In cancer, ADCYAP1 hypermethylation has been observed in epithelial ovarian cancer, correlating with tumor stage and HPV infection, suggesting a role in cancer progression. This epigenetic alteration is also noted in other cancers, such as cervical cancer, where it is associated with gene suppression (hassan2017human). The exact mechanisms by which ADCYAP1 contributes to carcinogenesis remain unclear, but its methylation status may serve as a diagnostic and prognostic biomarker (hassan2017human).

## Interactions
ADCYAP1, also known as PACAP, is involved in various interactions with proteins and receptors that play significant roles in physiological processes. It interacts with three G protein-coupled receptors: PAC1, VPAC1, and VPAC2. These interactions lead to the activation of adenylate cyclase, resulting in increased levels of cyclic AMP (cAMP), a crucial second messenger in cellular signaling (Chen2023Unveiling).

In the mouse brain, ADCYAP1 interacts notably with adenylate cyclase 7 (ADCY7), which is significant in the context of major depressive disorder. Disruptions in cAMP pathways, downstream of adenylate cyclases like ADCY7, are associated with psychiatric conditions such as depression, schizophrenia, and bipolar disorder (AcquaahMensah2012PACAP).

ADCYAP1 also interacts with glycogen synthase kinase-3beta (GSK3B), a relationship relevant to psychiatric disorders and the response to antidepressants and lithium in bipolar disorder treatment (AcquaahMensah2012PACAP). The interaction between ADCYAP1 and GSK3B is part of a complex regulatory network that may impact psychiatric conditions (AcquaahMensah2012PACAP).

Additionally, ADCYAP1 is involved in neuroimmune crosstalk, as its neurons express cytokine receptors, suggesting a role in linking infections, inflammation, and behavior (Ilanges2022Brainstem). These interactions highlight ADCYAP1's multifaceted role in neuroprotection, neurotransmission, and immune response modulation.


## References


[1. (Baskozos2020Molecular) Georgios Baskozos, Oliver Sandy-Hindmarch, Alex J Clark, Katherine Windsor, Pall Karlsson, Greg A Weir, Lucy A McDermott, Joanna Burchall, Akira Wiberg, Dominic Furniss, David L H Bennett, and Annina B Schmid. Molecular and cellular correlates of human nerve regeneration: adcyap1/pacap enhance nerve outgrowth. Brain, 143(7):2009–2026, July 2020. URL: http://dx.doi.org/10.1093/brain/awaa163, doi:10.1093/brain/awaa163. This article has 45 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1093/brain/awaa163)

[2. (Mansouri2017PACAP) Shiva Mansouri, Ingrid Agartz, Sven-Ove Ögren, Cesare Patrone, and Mathias Lundberg. Pacap protects adult neural stem cells from the neurotoxic effect of ketamine associated with decreased apoptosis, er stress and mtor pathway activation. PLOS ONE, 12(1):e0170496, January 2017. URL: http://dx.doi.org/10.1371/journal.pone.0170496, doi:10.1371/journal.pone.0170496. This article has 25 citations and is from a peer-reviewed journal.](https://doi.org/10.1371/journal.pone.0170496)

[3. (AcquaahMensah2012PACAP) George K. Acquaah-Mensah, Ronald C. Taylor, and Sanjiv V. Bhave. Pacap interactions in the mouse brain: implications for behavioral and other disorders. Gene, 491(2):224–231, January 2012. URL: http://dx.doi.org/10.1016/j.gene.2011.09.017, doi:10.1016/j.gene.2011.09.017. This article has 13 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.gene.2011.09.017)

4. (hassan2017human) Zeinab K Hassan, Mohamed M Hafez, Mahmoud M Kamel, and Abdel Rahman N Zekri. Human papillomavirus genotypes and methylation of cadm1, pax1, mal and adcyap1 genes in epithelial ovarian cancer patients. Asian Pacific journal of cancer prevention: APJCP, 18(1):169, 2017. This article has 31 citations.

[5. (Maugeri2020Effects) Grazia Maugeri, Agata Grazia D’Amico, Giuseppe Musumeci, Dora Reglodi, and Velia D’Agata. Effects of pacap on schwann cells: focus on nerve injury. International Journal of Molecular Sciences, 21(21):8233, November 2020. URL: http://dx.doi.org/10.3390/ijms21218233, doi:10.3390/ijms21218233. This article has 38 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/ijms21218233)

6. (Schmid2019Molecular) Molecular and cellular correlates of human nerve regeneration: ADCYAP1 encoding PACAP enhances sensory neuron outgrowth. This article has 0 citations.

[7. (Matsuzaki2008Regulation) Shinsuke Matsuzaki and Masaya Tohyama. Regulation of pituitary adenylyl cyclase-activating polypeptide (pacap, adcyap1: adenylyl cyclase-activating polypeptide 1) in the treatment of schizophrenia. Expert Opinion on Therapeutic Targets, 12(9):1097–1108, August 2008. URL: http://dx.doi.org/10.1517/14728222.12.9.1097, doi:10.1517/14728222.12.9.1097. This article has 11 citations and is from a peer-reviewed journal.](https://doi.org/10.1517/14728222.12.9.1097)

[8. (Ilanges2022Brainstem) Anoj Ilanges, Rani Shiao, Jordan Shaked, Ji-Dung Luo, Xiaofei Yu, and Jeffrey M. Friedman. Brainstem adcyap1+ neurons control multiple aspects of sickness behaviour. Nature, 609(7928):761–771, September 2022. URL: http://dx.doi.org/10.1038/s41586-022-05161-7, doi:10.1038/s41586-022-05161-7. This article has 43 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41586-022-05161-7)

[9. (Chen2023Unveiling) Qi Chen, Xi-Yin Zhang, Yu-Pu Wang, Yun-Jie Fu, Feng Cao, Yi-Nuo Xu, Jin-Ge Kong, Na-Xi Tian, Yu Xu, and Yun Wang. Unveiling adcyap1 as a protective factor linking pain and nerve regeneration through single-cell rna sequencing of rat dorsal root ganglion neurons. BMC Biology, October 2023. URL: http://dx.doi.org/10.1186/s12915-023-01742-8, doi:10.1186/s12915-023-01742-8. This article has 2 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1186/s12915-023-01742-8)