Alternative titles; symbols
HGNC Approved Gene Symbol: ADCYAP1R1
Cytogenetic location: 7p14.3 Genomic coordinates (GRCh38): 7:31,052,308-31,111,474 (from NCBI)
Pituitary adenylate cyclase-activating polypeptide (PACAP, or ADCYAP1; 102980) is a hormone originally isolated from sheep hypothalamus on the basis of its ability to stimulate adenylate cyclase in rat anterior pituitary cell cultures (Arimura, 1992). PACAP is present not only in the central nervous system, but also in peripheral tissues, including gastrointestinal tract, adrenal gland, and testis. Its actions include stimulation of secretion of growth hormone (GH1; 139250), ACTH , catecholamines, and insulin, as well as other hormones. In addition, it appears to function as a neuromodulator/neurotransmitter in the central and peripheral nervous systems. The diverse biologic actions of PACAP are mediated by receptors that are positively coupled to adenylate cyclase by Gs-alpha (see 139320). PACAP receptors contain 7 transmembrane segments and share significant homology with members of the glucagon/secretin receptor family. The type 1 PACAP receptor, ADCYAPR1, is found in hypothalamus, brainstem, pituitary, adrenal gland, pancreas, and testis, and has a high affinity only for PACAP (summary by Stoffel et al., 1994).
Ogi et al. (1993) cloned human ADCYAP1R1 from a pituitary cDNA library. The deduced 525-amino acid protein has a 78-amino acid N-terminal signal sequence, cleavage of which produces a mature 448-amino acid protein with a calculated molecular mass of 51.4 kD. ADCYAP1R1 contains 7 hydrophobic segments and 6 potential N-glycosylation sites. The full-length human ADCYAP1R1 protein shares 92.5% amino acid identity with its rat ortholog and 55.3% identity with human VIPR1 (192321). Northern blot analysis of human tissues detected a 7-kp ADCYAP1R1 transcript expressed abundantly in brain, with low expression in lung, liver, thymus, spleen, pancreas, and placenta.
Yon et al. (1998) found that type I PACAP receptors are present in the early stages of the human medulla organization during the process of migration of chromaffin cells from the periphery to the central part of the adrenal gland. They concluded that PACAP could be involved in the regulation of the human adrenochromaffin cells during ontogenesis.
By somatic cell hybrid analysis, Ogi et al. (1993) mapped the ADCYAP1R1 gene to chromosome 7.
By PCR analysis of genomic DNA from a human/rodent somatic cell hybrid mapping panel, Stoffel et al. (1994) mapped the ADCYAP1R1 gene to chromosome 7. They confirmed the assignment and localized the gene to chromosome 7p14 by fluorescence in situ hybridization. Brabet et al. (1996) likewise mapped this gene to chromosome 7p15-p14 by fluorescence in situ hybridization.
Using transfected CHO cells, Ogi et al. (1993) confirmed that human ADCYAP1R1 bound PACAP and mediated PACAP-triggered intracellular accumulation of cAMP.
PACAP is present in gastric nerves. PACAP receptors have been demonstrated on functional enterochromaffin-like (ECL) cells from the rat gastric mucosa. Zeng et al. (1999) presented results suggesting that PACAP is a candidate for a mediator of neural regulation of acid secretion.
Mercer et al. (2004) found that cultured neural stem cells isolated from the lateral ventricle wall of adult mice expressed Pac1 and proliferated in vitro in response to the Pac1 agonists Pacap and maxadilan, but not Vip (192320), at physiologic concentrations, indicating that Pac1 is a mediator of neural stem cell proliferation. Pharmacologic and biochemical characterization of Pacap-induced neural stem cell proliferation revealed that protein kinase C (see PRKCA, 176960) signaling was the principal pathway activated, and addition of Egf (131530) synergistically enhanced the proliferating effect of Pacap.
Associations Pending Confirmation
For discussion of a possible association between variation in the ADCYAP1R1 gene and susceptibility to posttraumatic stress disorder (PTSD), see 607834.
Lang et al. (2006) generated transgenic mice overexpressing Pac1 and observed development of dose-dependent hydrocephalus-like characteristics, including enlarged third and lateral ventricles and reduced cerebral cortex, corpus callosum, and subcommissural organ. There was also significantly reduced neuronal proliferation and massively increased neuronal apoptosis in the developing cortex and subcommissural organ of transgenic embryos, whereas neurite outgrowth and neuronal migration in vitro remained uncompromised; and the ependyma of transgenic mice exhibited disrupted cilia. Lang et al. (2006) concluded that misregulation of G protein-coupled receptors can be involved in hydrocephalus-related neurodevelopmental disorders.
Arimura, A. Pituitary adenylate cyclase activating polypeptide (PACAP): discovery and current status of research. Regul. Pept. 37: 287-303, 1992. [PubMed: 1313597]
Brabet, P., Diriong, S., Journot, L., Bockaert, J., Taviaux, S. Localization of the human pituitary adenylate cyclase-activating polypeptide receptor (PACAP-1-R) gene to 7p15-p14 by fluorescence in situ hybridization. Genomics 38: 100-102, 1996. [PubMed: 8954788] [Full Text: https://doi.org/10.1006/geno.1996.0600]
Lang, B., Song, B., Davidson, W., MacKenzie, A., Smith, N., McCaig, C. D., Harmar, A. J., Shen, S. Expression of the human PAC1 receptor leads to dose-dependent hydrocephalus-related abnormalities in mice. J. Clin. Invest. 116: 1924-1934, 2006. [PubMed: 16823490] [Full Text: https://doi.org/10.1172/JCI27597]
Mercer, A., Ronnholm, H., Holmberg, J., Lundh, H., Heidrich, J., Zachrisson, O., Ossoinak, A., Frisen, J., Patrone, C. PACAP promotes neural stem cell proliferation in adult mouse brain. J. Neurosci. Res. 76: 205-215, 2004. [PubMed: 15048918] [Full Text: https://doi.org/10.1002/jnr.20038]
Ogi, K., Miyamoto, Y., Masuda, Y., Habata, Y., Hosoya, M., Ohtaki, T., Masuo, Y., Onda, H., Fujino, M. Molecular cloning and functional expression of a cDNA encoding a human pituitary adenylate cyclase activating polypeptide receptor. Biochem. Biophys. Res. Commun. 196: 1511-1521, 1993. [PubMed: 7902709] [Full Text: https://doi.org/10.1006/bbrc.1993.2423]
Stoffel, M., Espinosa, R., III, Trabb, J. B., Le Beau, M. M., Bell, G. I. Human type I pituitary adenylate cyclase activating polypeptide receptor (ADCYAP1R): localization to chromosome band 7p14 and integration into the cytogenetic, physical, and genetic map of chromosome 7. Genomics 23: 697-699, 1994. [PubMed: 7851900] [Full Text: https://doi.org/10.1006/geno.1994.1560]
Yon, L., Breault, L., Contesse, V., Bellancourt, G., Delarue, C., Fournier, A., Lehoux, J.-G., Vaudry, H., Gallo-Payet, N. Localization, characterization, and second messenger coupling of pituitary adenylate cyclase-activating polypeptide receptors in the fetal human adrenal gland during the second trimester of gestation. J. Clin. Endocr. Metab. 83: 1299-1305, 1998. [PubMed: 9543159] [Full Text: https://doi.org/10.1210/jcem.83.4.4690]
Zeng, N., Athmann, C., Kang, T., Lyu, R.-M., Walsh, J. H., Ohning, G. V., Sachs, G., Pisegna, J. R. PACAP type I receptor activation regulates ECL cells and gastric acid secretion. J. Clin. Invest. 104: 1383-1391, 1999. [PubMed: 10562300] [Full Text: https://doi.org/10.1172/JCI7537]