HGNC Approved Gene Symbol: VIPR2
Cytogenetic location: 7q36.3 Genomic coordinates (GRCh38): 7:159,028,175-159,144,867 (from NCBI)
VIPR2 and VIPR1 (192321) encode receptors for the neuropeptide vasoactive intestinal peptide (VIP; 192320), and also bind pituitary adenylate cyclase activating polypeptide (PACAP; 102980) with affinity equal to that for VIP. While the receptors for VIP and PACAP share homology, they differ in their substrate specificities and expression patterns (summary by Mackay et al., 1996).
Svoboda et al. (1994) performed low-stringency PCR using primers based on sequences conserved among VIP receptors. They cloned the human VIP2 receptor gene from a lymphoblast cDNA library. This gene encodes a 438-amino acid polypeptide that shares 86% identity with the rat VIP2 receptor.
Adamou et al. (1995) cloned the VIP2 receptor gene from a human placenta cDNA library. Northern blot analysis revealed that VIPR2 is expressed as 2 transcripts of 4.6 kb and 2.3 kb at high levels in skeletal muscle and at lower levels in heart, brain, placenta, and pancreas.
Svoboda et al. (1994) expressed the human VIP2 receptor in Chinese hamster ovary cells and found that it binds to PACAP38 and PACAP27 (see 102980), VIP, and helodermin, and that binding of the receptor to any of these peptides activates adenylate cyclase. Peptide binding was found to be inhibited by GTP.
Talbot et al. (2020) showed in mice how a gut neuronal signal triggered by food intake is integrated with intestinal antimicrobial and metabolic responses that are controlled by type 3 innate lymphoid cells (ILC3). Food consumption rapidly activates a population of enteric neurons that express VIP. Projections of VIP-producing neurons in the lamina propria are in close proximity to clusters of ILC3 that selectively express VIPR2. Production of IL22 (192320) by ILC3, which is upregulated by the presence of commensal microorganisms such as segmented filamentous bacteria, is inhibited upon engagement of VIPR2. As a consequence, levels of antimicrobial peptide derived from epithelial cells are reduced but the expression of lipid-binding proteins and transporters is increased. During food consumption, the activation of VIP-producing neurons thus enhances the growth of segmented filamentous bacteria associated with the epithelium, and increases lipid absorption. Talbot et al. (2020) concluded that their results revealed a feeding- and circadian-regulated dynamic neuroimmune circuit in the intestine that promotes a trade-off between innate immune protection mediated by IL22 and the efficiency of nutrient absorption.
Mackay et al. (1996) used fluorescence in situ hybridization to map the VIPR2 gene to human chromosome 7q36.3. Further mapping with cell lines derived from patients with holoprosencephaly type 3 (HPE3; 142945) revealed that the VIPR2 gene lies within the HPE3 minimal critical region. Mackay et al. (1996) stated that although VIPR2 may contribute to the HPE3 phenotype, it is not the sole factor responsible.
Vacic et al. (2011) performed a large 2-stage genomewide scan of rare copy number variants (CNVs) and reported the significant association of copy number gains at chromosome 7q36.3 with schizophrenia (SCZD16; 613959). Microduplications with variable breakpoints occurred within a 362-kb region and were detected in 29 of 8,290 (0.35%) patients versus 2 of 7,431 (0.03%) controls in the combined sample. All duplications overlapped or were located within 89 kb upstream of the vasoactive intestinal peptide receptor gene VIPR2. VIPR2 transcription and cyclic AMP signaling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. Vacic et al. (2011) concluded that their findings implicated altered vasoactive intestinal peptide signaling in the pathogenesis of schizophrenia and indicated the VPAC2 receptor as a potential target for the development of antipsychotic drugs.
Harmar et al. (2002) reported that Vipr2 -/- mice were incapable of sustaining normal circadian rhythms of rest/activity behavior. These mice also failed to exhibit circadian expression of the core clock genes Per1 (602260), Per2 (603426), and Cry1 (601933) and the clock-controlled gene encoding arginine vasopressin (AVP; 192340) in the suprachiasmatic nuclei. Moreover, the mutants failed to show acute induction of Per1 and Per2 by nocturnal illumination.
Adamou, J. E., Aiyar, N., Van Horn, S., Elshourbagy, N. A. Cloning and functional characterization of the human vasoactive intestinal peptide (VIP)-2 receptor. Biochem. Biophys. Res. Commun. 209: 385-392, 1995. [PubMed: 7733904] [Full Text: https://doi.org/10.1006/bbrc.1995.1515]
Harmar, A. J., Marston, H. M., Shen, S., Spratt, C., West, K. M., Sheward, W. J., Morrison, C. F., Dorin, J. R., Piggins, H. D., Reubi, J.-C., Kelly, J. S., Maywood, E. S., Hastings, M. H. The VPAC2 receptor is essential for circadian function in the mouse suprachiasmatic nuclei. Cell 109: 497-508, 2002. [PubMed: 12086606] [Full Text: https://doi.org/10.1016/s0092-8674(02)00736-5]
Mackay, M., Fantes, J., Scherer, S., Boyle, S., West, K., Tsui, L.-C., Belloni, E., Lutz, E., Van Heyningen, V., Harmar, A. J. Chromosomal localization in mouse and human of the vasoactive intestinal peptide receptor type 2 gene: a possible contributor to the holoprosencephaly 3 phenotype. Genomics 37: 345-353, 1996. [PubMed: 8938447] [Full Text: https://doi.org/10.1006/geno.1996.0569]
Svoboda, M., Tastenoy, M., Van Rampelbergh, J., Goossens, J.-F., De Neef, P., Waelbroeck, M., Robberecht, P. Molecular cloning and functional characterization of a human VIP receptor from SUP-T1 lymphoblasts. Biochem. Biophys. Res. Commun. 205: 1617-1624, 1994. [PubMed: 7811244] [Full Text: https://doi.org/10.1006/bbrc.1994.2852]
Talbot, J., Hahn, P., Kroehling, L., Nguyen, H., Li, D., Littman, D. R. Feeding-dependent VIP neuron-ILC3 circuit regulates the intestinal barrier. Nature 579: 575-580, 2020. [PubMed: 32050257] [Full Text: https://doi.org/10.1038/s41586-020-2039-9]
Vacic, V., McCarthy, S. Malhotra, D., Murray, F., Chou, H.-H., Peoples, A., Makarov, V., Yoon, S., Bhandari, A., Corominas, R., Iakoucheva, L. M., Krastoshevsky, O., and 18 others. Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia. Nature 471: 499-503, 2011. Note: Erratum: Nature 474: 114 only, 2011. [PubMed: 21346763] [Full Text: https://doi.org/10.1038/nature09884]