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Gene Review

Adcyap1  -  adenylate cyclase activating polypeptide 1

Mus musculus

Synonyms: PACAP, Pacap, Pituitary adenylate cyclase-activating polypeptide
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Disease relevance of Adcyap1

  • Anti-inflammatory role in septic shock of pituitary adenylate cyclase-activating polypeptide receptor [1].
  • Overexpression of PKCbetaII with adenovirus vector synergistically enhanced differentiation in the presence of 1 nM PACAP, whereas expression of the dominant-negative mutant of PKCbetaII proved inhibitory [2].
  • We suggest that VIP and PACAP contribute to the developing metabolic syndrome in ob/ob mice by aggravating hyperinsulinemia [3].
  • The present study was designed to investigate the role played by PACAP and IL-6 in mediating neuroprotection after ischemia in a null mouse [4].
  • However, insulin-induced hypoglycemia was more profound and longer-lasting in PACAP knock-outs, and was associated with a dose-related lethality absent in wild-type mice [5].

Psychiatry related information on Adcyap1


High impact information on Adcyap1

  • We now report that mice carrying a null mutation of the VPAC(2) receptor for VIP and PACAP (Vipr2(-/-)) are incapable of sustaining normal circadian rhythms of rest/activity behavior [11].
  • The neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are implicated in the photic entrainment of circadian rhythms in the suprachiasmatic nuclei (SCN) [11].
  • The pituitary adenylate cyclase-activating polypeptide is a physiological inhibitor of platelet activation [12].
  • Pituitary adenylate cyclase-activating polypeptide (PACAP) is a ubiquitous neuropeptide of the vasoactive intestinal peptide (VIP) family that potentiates glucose-stimulated insulin secretion [13].
  • Expression of a dominant-negative mutant (KCREB) of the CRE-binding factor CREB markedly diminished trans-activation of the chromogranin A promoter by PACAP [14].

Chemical compound and disease context of Adcyap1


Biological context of Adcyap1

  • These original data demonstrate that functional GPCRs for VIP and PACAP are present on ES cells and that these neuropeptides may induce their differentiation into a neuronal phenotype [18].
  • The 5'-flanking region of the PACAP gene contains several sequence motifs homologous to cAMP response element, TPA response element, and growth hormone factor-1 binding site [19].
  • The PACAP gene spans 6.6kb of genomic DNA and is composed of six exons including the alternative exons [19].
  • Promoter analysis of the 5'-flanking region of the PACAP gene using a luciferase gene reporter system revealed that the isolated 5'-flanking region has functional promoter activity and is responsible for inducible expression [19].
  • Although we were unable to detect gross effects of either peptide on the growth rates of embryos maintained in culture, mRNAs for both PAC1 receptor and PACAP peptide were present in the nervous system from day 9.5 of embryonic development [20].

Anatomical context of Adcyap1


Associations of Adcyap1 with chemical compounds

  • Absence of pituitary adenylate cyclase-activating polypeptide-stimulated transcription of the human glycoprotein alpha-subunit gene in LbetaT2 gonadotrophs reveals disrupted cAMP-mediated gene transcription [21].
  • We have found previously that pituitary adenylate cyclase-activating polypeptide (PACAP) increases the number of astrocytes generated from cultured mouse neural stem cells (NSCs) via a mechanism that is independent of the cyclic AMP/protein kinase A pathway (Ohno et al., 2005) [2].
  • PACAP-induced differentiation was inhibited by the phospholipase C inhibitor, U73122, the protein kinase C (PKC) inhibitor, chelerythrine, and the intracellular calcium chelator, BAPTA-AM, and was mimicked by phorbol 12-myristate 13-acetate (PMA), but not by 4alpha-PMA [2].
  • Theophylline (1 mg/kg, i.p.) pretreatment significantly enhanced the effect of PACAP on morphine analgesia but the effects of PACAP on tolerance and withdrawal were unaffected upon theophylline administration [23].
  • VIP did not increase 11.1mM glucose-induced insulin release in islets from 4-week-old lean normoglycemic mice and neither did PACAP in the absence of bicarbonate [3].

Physical interactions of Adcyap1

  • This possibility is supported by the observation that cytosolic endogenous PACAP in spermatids was co-immunoprecipitated with the cytosolic PAC1-R [24].
  • VIP/PACAP binding to VPAC1 induces both a cAMP-dependent and a cAMP-independent pathways that regulate cytokine and NO production at the transcriptional level [25].
  • We showed previously that VIP/PACAP change the composition of the CRE-binding complex in the TNFalpha promoter from highc-Jun/(low)CREB, characteristic for LPS-stimulated macrophages, to lowc-Jun/(high)CREB, characteristic for the unstimulated cells [26].

Regulatory relationships of Adcyap1


Other interactions of Adcyap1

  • Mouse ES cells were allowed to aggregate in embryoid bodies (EBs) in the presence or not of VIP and PACAP for 1 week [18].
  • The VIP/PACAP interference with the p65/CBP interaction in activated microglia may represent a significant element in the regulation of the inflammatory response in the CNS by the endogenous neuropeptides [22].
  • Within the neural tube, PAC1 receptor mRNA was located in the roof and floor plates, while the distribution of PACAP peptide mRNA was more complex, being located in two columns of cells in the ventromedial neural tube (consistent with the position of developing autonomic motor neurons) and in cells in the dorsolateral neural tube [20].
  • The vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), two immunomodulatory neuropeptides, act as anti-inflammatory factors for activated microglia, by inhibiting the production of pro-inflammatory factors, mainly mediated through the inhibition of NF-kappaB nuclear translocation and DNA binding [22].
  • The neuropeptide PACAP contributes to the glucagon response to insulin-induced hypoglycaemia in mice [28].

Analytical, diagnostic and therapeutic context of Adcyap1

  • LbetaT2 gonadotrophs expressed extremely low levels of any PACAP type 1 receptors (PAC(1)-R) isoform by RT-PCR and lacked PAC(1)-R by radioligand binding [21].
  • The effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on pain sensitivity, on morphine analgesia, on morphine tolerance and withdrawal were investigated in mice [23].
  • Pituitary adenylate cyclase-activating polypeptide (PACAP) isolated from ovine hypothalamic tissue is a novel neuropeptide which stimulates adenylate cyclase in rat anterior pituitary cell cultures [31].
  • Because functional defects have been demonstrated in the large islets of obese animal models, together these findings suggest that PACAP regulates hyperinsulinemia and the abnormal increase in islet mass that occurs during the diabetic process [30].
  • Using in situ hybridization and polymerase chain reaction, we show that in situ and in neurointermediate lobe explants, melanotropes express PACAP receptor type I isoforms that transduce through the cAMP and inositol phosphate pathways [32].


  1. Anti-inflammatory role in septic shock of pituitary adenylate cyclase-activating polypeptide receptor. Martinez, C., Abad, C., Delgado, M., Arranz, A., Juarranz, M.G., Rodriguez-Henche, N., Brabet, P., Leceta, J., Gomariz, R.P. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  2. Pituitary adenylate cyclase-activating polypeptide-induced differentiation of embryonic neural stem cells into astrocytes is mediated via the beta isoform of protein kinase C. Watanabe, J., Ohba, M., Ohno, F., Kikuyama, S., Nakamura, M., Nakaya, K., Arimura, A., Shioda, S., Nakajo, S. J. Neurosci. Res. (2006) [Pubmed]
  3. Vasoactive intestinal polypeptide and pituitary adenylate cyclase activating polypeptide: Effects on insulin release in isolated mouse islets in relation to metabolic status and age. Persson-Sjögren, S., Forsgren, S., Lindström, P. Neuropeptides (2006) [Pubmed]
  4. Pituitary adenylate cyclase-activating polypeptide (PACAP) decreases ischemic neuronal cell death in association with IL-6. Ohtaki, H., Nakamachi, T., Dohi, K., Aizawa, Y., Takaki, A., Hodoyama, K., Yofu, S., Hashimoto, H., Shintani, N., Baba, A., Kopf, M., Iwakura, Y., Matsuda, K., Arimura, A., Shioda, S. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  5. Pituitary adenylate cyclase-activating polypeptide is a sympathoadrenal neurotransmitter involved in catecholamine regulation and glucohomeostasis. Hamelink, C., Tjurmina, O., Damadzic, R., Young, W.S., Weihe, E., Lee, H.W., Eiden, L.E. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  6. Psychostimulant-induced attenuation of hyperactivity and prepulse inhibition deficits in Adcyap1-deficient mice. Tanaka, K., Shintani, N., Hashimoto, H., Kawagishi, N., Ago, Y., Matsuda, T., Hashimoto, R., Kunugi, H., Yamamoto, A., Kawaguchi, C., Shimada, T., Baba, A. J. Neurosci. (2006) [Pubmed]
  7. PACAP deficient mice display reduced carbohydrate intake and PACAP activates NPY-containing neurons in the rat hypothalamic arcuate nucleus. Nakata, M., Kohno, D., Shintani, N., Nemoto, Y., Hashimoto, H., Baba, A., Yada, T. Neurosci. Lett. (2004) [Pubmed]
  8. Defects in reproductive functions in PACAP-deficient female mice. Shintani, N., Mori, W., Hashimoto, H., Imai, M., Tanaka, K., Tomimoto, S., Hirose, M., Kawaguchi, C., Baba, A. Regul. Pept. (2002) [Pubmed]
  9. Selective deficits in the circadian light response in mice lacking PACAP. Colwell, C.S., Michel, S., Itri, J., Rodriguez, W., Tam, J., Lelièvre, V., Hu, Z., Waschek, J.A. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2004) [Pubmed]
  10. Altered social behavior in pituitary adenylate cyclase-activating polypeptide type I receptor-deficient mice. Nicot, A., Otto, T., Brabet, P., Dicicco-Bloom, E.M. J. Neurosci. (2004) [Pubmed]
  11. The VPAC(2) receptor is essential for circadian function in the mouse suprachiasmatic nuclei. 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. Cell (2002) [Pubmed]
  12. The pituitary adenylate cyclase-activating polypeptide is a physiological inhibitor of platelet activation. Freson, K., Hashimoto, H., Thys, C., Wittevrongel, C., Danloy, S., Morita, Y., Shintani, N., Tomiyama, Y., Vermylen, J., Hoylaerts, M.F., Baba, A., Van Geet, C. J. Clin. Invest. (2004) [Pubmed]
  13. PAC1 receptor-deficient mice display impaired insulinotropic response to glucose and reduced glucose tolerance. Jamen, F., Persson, K., Bertrand, G., Rodriguez-Henche, N., Puech, R., Bockaert, J., Ahrén, B., Brabet, P. J. Clin. Invest. (2000) [Pubmed]
  14. Peptidergic activation of transcription and secretion in chromaffin cells. Cis and trans signaling determinants of pituitary adenylyl cyclase-activating polypeptide (PACAP). Taupenot, L., Mahata, S.K., Wu, H., O'Connor, D.T. J. Clin. Invest. (1998) [Pubmed]
  15. Endogenous PACAP acts as a stress response peptide to protect cerebellar neurons from ethanol or oxidative insult. Vaudry, D., Hamelink, C., Damadzic, R., Eskay, R.L., Gonzalez, B., Eiden, L.E. Peptides (2005) [Pubmed]
  16. The effect of cardiac arrest on the blood-testis barrier to albumin, tumor necrosis factor-alpha, pituitary adenylate cyclase activating polypeptide, sucrose, and verapamil in the mouse. Mizushima, H., Nakamura, Y., Matsumoto, H., Dohi, K., Matsumoto, K., Shioda, S., Banks, W.A. J. Androl. (2001) [Pubmed]
  17. PACAP-type IB receptors mediate stimulation of phosphoinositide metabolism in mouse neuroblastoma cells, clone N1E-115. Taylor, J.E. Ann. N. Y. Acad. Sci. (1996) [Pubmed]
  18. VIP and PACAP induce selective neuronal differentiation of mouse embryonic stem cells. Cazillis, M., Gonzalez, B.J., Billardon, C., Lombet, A., Fraichard, A., Samarut, J., Gressens, P., Vaudry, H., Rostène, W. Eur. J. Neurosci. (2004) [Pubmed]
  19. Cloning and characterization of the mouse pituitary adenylate cyclase-activating polypeptide (PACAP) gene. Yamamoto, K., Hashimoto, H., Hagihara, N., Nishino, A., Fujita, T., Matsuda, T., Baba, A. Gene (1998) [Pubmed]
  20. Expression of PACAP, and PACAP type 1 (PAC1) receptor mRNA during development of the mouse embryo. Sheward, W.J., Lutz, E.M., Copp, A.J., Harmar, A.J. Brain Res. Dev. Brain Res. (1998) [Pubmed]
  21. Absence of pituitary adenylate cyclase-activating polypeptide-stimulated transcription of the human glycoprotein alpha-subunit gene in LbetaT2 gonadotrophs reveals disrupted cAMP-mediated gene transcription. Fowkes, R.C., Sidhu, K.K., Sosabowski, J.K., King, P., Burrin, J.M. J. Mol. Endocrinol. (2003) [Pubmed]
  22. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit CBP-NF-kappaB interaction in activated microglia. Delgado, M. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  23. The effects of pituitary adenylate cyclase-activating polypeptide on acute and chronic morphine actions in mice. Mácsai, M., Pataki, I., Tóth, G., Szabó, G. Regul. Pept. (2002) [Pubmed]
  24. Pituitary adenylate cyclase activating polypeptide-mediated intracrine signaling in the testicular germ cells. Li, M., Funahashi, H., Mbikay, M., Shioda, S., Arimura, A. Endocrine (2004) [Pubmed]
  25. Receptors and transcriptional factors involved in the anti-inflammatory activity of VIP and PACAP. Leceta, J., Gomariz, R.P., Martinez, C., Abad, C., Ganea, D., Delgado, M. Ann. N. Y. Acad. Sci. (2000) [Pubmed]
  26. Vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide inhibit the MEKK1/MEK4/JNK signaling pathway in LPS-stimulated macrophages. Delgado, M., Ganea, D. J. Neuroimmunol. (2000) [Pubmed]
  27. Modulation of NMDA receptors by pituitary adenylate cyclase activating peptide in CA1 neurons requires G alpha q, protein kinase C, and activation of Src. Macdonald, D.S., Weerapura, M., Beazely, M.A., Martin, L., Czerwinski, W., Roder, J.C., Orser, B.A., MacDonald, J.F. J. Neurosci. (2005) [Pubmed]
  28. The neuropeptide PACAP contributes to the glucagon response to insulin-induced hypoglycaemia in mice. Persson, K., Ahrén, B. Acta Physiol. Scand. (2002) [Pubmed]
  29. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit tumor necrosis factor alpha transcriptional activation by regulating nuclear factor-kB and cAMP response element-binding protein/c-Jun. Delgado, M., Munoz-Elias, E.J., Kan, Y., Gozes, I., Fridkin, M., Brenneman, D.E., Gomariz, R.P., Ganea, D. J. Biol. Chem. (1998) [Pubmed]
  30. Overexpression of pituitary adenylate cyclase-activating polypeptide in islets inhibits hyperinsulinemia and islet hyperplasia in agouti yellow mice. Tomimoto, S., Hashimoto, H., Shintani, N., Yamamoto, K., Kawabata, Y., Hamagami, K., Yamagata, K., Miyagawa, J., Baba, A. J. Pharmacol. Exp. Ther. (2004) [Pubmed]
  31. Pituitary adenylate cyclase-activating polypeptide induces cAMP production independently from vasoactive intestinal polypeptide in osteoblast-like cells. Suzuki, A., Kotoyori, J., Oiso, Y., Kozawa, O. Cell. Signal. (1994) [Pubmed]
  32. Pituitary adenylate cyclase-activating polypeptide transduces through cAMP/PKA and PKC pathways and stimulates proopiomelanocortin gene transcription in mouse melanotropes. René, F., Monnier, D., Gaiddon, C., Félix, J.M., Loeffler, J.P. Neuroendocrinology (1996) [Pubmed]
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