# VIPR1

## Overview
The VIPR1 gene encodes the vasoactive intestinal peptide receptor 1 (VIPR1), a class B G protein-coupled receptor (GPCR) involved in numerous physiological processes. This receptor is characterized by its seven transmembrane helices and an extracellular domain essential for ligand binding and activation. VIPR1 plays a critical role in mediating cellular responses to the vasoactive intestinal peptide, influencing smooth muscle relaxation, exocrine and endocrine secretion, and ion flux activities. It is predominantly expressed in lung and intestinal tissues but also participates in signaling pathways crucial for cardiovascular and nervous system functions. The receptor's interaction with G proteins and arrestins facilitates diverse signaling pathways, including those related to cyclic nucleotide second messengers and intracellular calcium levels (Duan2020Cryo-EM; Zhao2019Mechanism).

## Structure
The human VIPR1 gene encodes the Vasoactive Intestinal Peptide Receptor 1 (VIPR1), a class B G protein-coupled receptor (GPCR). This receptor features a characteristic seven transmembrane helices bundle and an extracellular domain (ECD) that forms the N-terminal cup of the receptor, typical for class B GPCRs (Latek2019A). The ECD is crucial for peptide binding and receptor activation, with specific residues such as Asp107, Gly116, Cys122, Lys127, and Gln135 playing significant roles in these processes (Latek2019A). Additionally, the receptor includes glycosylation sites at Asn58, Asn69, and Asn100, which are essential for its function and cellular localization (Latek2019A).

The VIPR1 receptor also contains a signal peptide necessary for its expression on the plasma membrane and features a sushi domain characterized by two antiparallel beta sheets stabilized by disulfide bonds and a salt bridge (Harmar2012Pharmacology). The intracellular part of the transmembrane bundle interacts with G proteins or arrestin through various residues, facilitating signaling pathways such as cAMP and intracellular calcium responses (Latek2019A).

The molecular dynamics studies and structural analyses, including cryo-electron microscopy, have provided insights into the receptor's interaction with ligands and its activation mechanism, although a complete high-resolution structure of VIPR1 remains unresolved (Duan2020Cryo-EM; Latek2019A). These studies highlight the dynamic nature of the ECD and its significant role in ligand recognition and receptor activation (Duan2020Cryo-EM).

## Function
VIPR1, or vasoactive intestinal peptide receptor 1, is a G protein-coupled receptor that plays a significant role in various physiological functions in healthy human cells. It is primarily involved in the relaxation of smooth muscle and the modulation of exocrine, endocrine, and ion flux activities, particularly in lung and intestinal epithelial cells (Zhao2019Mechanism). VIPR1 is also implicated in the regulation of cyclic-nucleotide-mediated signaling, G protein-coupled receptor signaling pathway coupled to cyclic nucleotide second messenger, and adenylate cyclase-activating G protein-coupled receptor signaling pathway. These pathways are crucial for maintaining cellular homeostasis and responding to physiological stimuli (Lin2022lncRNA-AC079061.1/VIPR1).

In terms of cellular location, VIPR1 and its related genes are suggested to be located in the perikaryon, endocytic vesicle membrane, and mitochondria-associated ER membrane, indicating a role in cellular trafficking and signaling transduction mechanisms (Lin2022lncRNA-AC079061.1/VIPR1). The molecular function of VIPR1 includes peptide hormone binding and G protein-coupled peptide receptor activity, which are essential for peptide-mediated cellular responses (Lin2022lncRNA-AC079061.1/VIPR1).

Overall, VIPR1 is integral to a range of cellular processes that contribute to the normal physiological functioning of human tissues, particularly in the cardiovascular and nervous systems. Its activity is crucial for the regulation of various molecular pathways that influence cellular communication and response to hormonal signals.

## Clinical Significance
VIPR1, or vasoactive intestinal peptide receptor 1, has been implicated in various human diseases, particularly in different types of cancer. In lung adenocarcinoma, lower expression levels of VIPR1 mRNA are associated with poorer survival outcomes, indicating its potential role as a prognostic marker (Li2021Analysis). Similarly, in hepatocellular carcinoma (HCC), VIPR1 expression is generally reduced and correlates with poor histological differentiation and adverse survival rates. This suggests that VIPR1 may act as a tumor suppressor in this context (Lu2019Promoter). Furthermore, the gene's expression is influenced by epigenetic modifications such as methylation and histone deacetylation, particularly deacetylation of H3K27, which inhibits its transcription in HCC (Lu2019Promoter).

Beyond its role in cancer, VIPR1 is also involved in immune modulation. Variations in the VIPR1 gene, such as specific polymorphisms, have been linked to altered immune responses and may influence the progression of inflammatory and autoimmune diseases. For instance, the rs896 polymorphism in VIPR1 affects the kinetics of mRNA downregulation in monocytes, which is crucial for the anti-inflammatory response (Paladini2008A). This gene's diverse roles in both oncological and immunological contexts underscore its clinical significance in human health and disease.

## Interactions
VIPR1, encoded by the VIPR1 gene, is a receptor for vasoactive intestinal peptide (VIP) and participates in various protein-protein interactions crucial for its signaling functions. It interacts with G proteins and arrestin, which are essential for mediating its effects in signaling pathways such as cAMP and intracellular calcium response (Latek2019A). Specifically, residues K322 (ICL3) and E394 (TMH7) of VIPR1 are involved in interactions with the G alpha subunit, either directly or indirectly, facilitating the activation of the cAMP pathway (Latek2019A). Additionally, segments I328-R329-K330-S331 (proximal) and R338-L339 (distal) in ICL3 are crucial for the interactions between VIPR1 and G alpha, which are important for the intracellular calcium response (Latek2019A).

VIPR1 also undergoes rapid phosphorylation and internalization upon agonist exposure, involving interactions with kinases such as PKC and GRK. This internalization can activate G protein-independent signaling pathways, such as the PI3K/Akt and MAPK pathways (Langer2022Signal). Furthermore, VIPR1 is involved in the activation of several kinases and signaling pathways, including pathways involving PKA, CamK, and ERK, which play roles in cell differentiation and neurotransmitter secretion in the hypothalamus (Langer2022Signal). These interactions highlight the multifaceted role of VIPR1 in cellular signaling and physiological processes.


## References


[1. (Duan2020Cryo-EM) Jia Duan, Dan-dan Shen, X. Edward Zhou, Peng Bi, Qiu-feng Liu, Yang-xia Tan, You-wen Zhuang, Hui-bing Zhang, Pei-yu Xu, Si-Jie Huang, Shan-shan Ma, Xin-heng He, Karsten Melcher, Yan Zhang, H. Eric Xu, and Yi Jiang. Cryo-em structure of an activated vip1 receptor-g protein complex revealed by a nanobit tethering strategy. Nature Communications, August 2020. URL: http://dx.doi.org/10.1038/s41467-020-17933-8, doi:10.1038/s41467-020-17933-8. (137 citations) 10.1038/s41467-020-17933-8](https://doi.org/10.1038/s41467-020-17933-8)

[2. (Zhao2019Mechanism) Lufeng Zhao, Zipu Yu, and Baiqin Zhao. Mechanism of vipr1 gene regulating human lung adenocarcinoma h1299 cells. Medical Oncology, September 2019. URL: http://dx.doi.org/10.1007/s12032-019-1312-y, doi:10.1007/s12032-019-1312-y. (25 citations) 10.1007/s12032-019-1312-y](https://doi.org/10.1007/s12032-019-1312-y)

[3. (Lin2022lncRNA-AC079061.1/VIPR1) Xia-Hui Lin, Dan-Ying Zhang, Zhi-Yong Liu, Wen-qing Tang, Rong-Xin Chen, Dong-ping Li, Shuqiang Weng, and Ling Dong. Lncrna-ac079061.1/vipr1 axis may suppress the development of hepatocellular carcinoma: a bioinformatics analysis and experimental validation. Journal of Translational Medicine, August 2022. URL: http://dx.doi.org/10.1186/s12967-022-03573-7, doi:10.1186/s12967-022-03573-7. (2 citations) 10.1186/s12967-022-03573-7](https://doi.org/10.1186/s12967-022-03573-7)

[4. (Latek2019A) Dorota Latek, Ingrid Langer, Krystiana Krzysko, and Lukasz Charzewski. A molecular dynamics study of vasoactive intestinal peptide receptor 1 and the basis of its therapeutic antagonism. International Journal of Molecular Sciences, 20(18):4348, September 2019. URL: http://dx.doi.org/10.3390/ijms20184348, doi:10.3390/ijms20184348. (13 citations) 10.3390/ijms20184348](https://doi.org/10.3390/ijms20184348)

[5. (Li2021Analysis) Analysis of the Expression and Clinical Significance of VIPR1 in Lung Adenocarcinoma Based on TCGA Database (0 citations) 10.21203/rs.3.rs-1058170/v1](https://doi.org/10.21203/rs.3.rs-1058170/v1)

[6. (Paladini2008A) F Paladini, E Cocco, A Cauli, I Cascino, A Vacca, F Belfiore, M T Fiorillo, A Mathieu, and R Sorrentino. A functional polymorphism of the vasoactive intestinal peptide receptor 1 gene correlates with the presence of hla-b *2705 in sardinia. Genes & Immunity, 9(8):659–667, July 2008. URL: http://dx.doi.org/10.1038/gene.2008.60, doi:10.1038/gene.2008.60. (41 citations) 10.1038/gene.2008.60](https://doi.org/10.1038/gene.2008.60)

[7. (Langer2022Signal) Ingrid Langer, Jérôme Jeandriens, Alain Couvineau, Swapnil Sanmukh, and Dorota Latek. Signal transduction by vip and pacap receptors. Biomedicines, 10(2):406, February 2022. URL: http://dx.doi.org/10.3390/biomedicines10020406, doi:10.3390/biomedicines10020406. (28 citations) 10.3390/biomedicines10020406](https://doi.org/10.3390/biomedicines10020406)

[8. (Lu2019Promoter) Sicong Lu, Haiming Lu, Rongzhong Jin, and Zhijing Mo. Promoter methylation and h3k27 deacetylation regulate the transcription of vipr1 in hepatocellular carcinoma. Biochemical and Biophysical Research Communications, 509(1):301–305, January 2019. URL: http://dx.doi.org/10.1016/j.bbrc.2018.12.129, doi:10.1016/j.bbrc.2018.12.129. (15 citations) 10.1016/j.bbrc.2018.12.129](https://doi.org/10.1016/j.bbrc.2018.12.129)

[9. (Harmar2012Pharmacology) Anthony J Harmar, Jan Fahrenkrug, Illana Gozes, Marc Laburthe, Victor May, Joseph R Pisegna, David Vaudry, Hubert Vaudry, James A Waschek, and Sami I Said. Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase‐activating polypeptide: iuphar review 1. British Journal of Pharmacology, 166(1):4–17, April 2012. URL: http://dx.doi.org/10.1111/j.1476-5381.2012.01871.x, doi:10.1111/j.1476-5381.2012.01871.x. (362 citations) 10.1111/j.1476-5381.2012.01871.x](https://doi.org/10.1111/j.1476-5381.2012.01871.x)