*102980	Links
ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE 1; ADCYAP1

Alternative titles; symbols

PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE; PACAP
PACAP38, INCLUDED
PACAP27, INCLUDED
PACAP-RELATED PEPTIDE, INCLUDED; PRP, INCLUDED

Gene map locus 18p11

TEXT

CLONING

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a bioactive peptide that was originally isolated from ovine hypothalamus on the basis of its ability to stimulate adenylate cyclase in rat anterior pituitary cell cultures. The N-terminal amino acid sequence of PACAP shares 68% identity with vasoactive intestinal peptide (VIP; 192320) and more limited similarity with growth hormone-releasing hormone (GHRH; 139190). Hosoya et al. (1992) cloned human PACAP. The deduced 176-amino acid precursor protein contains an N-terminal signal peptide, a central PACAP-related peptide (PRP) sequence, and the C-terminal bioactive peptide sequence. There are 2 mature PACAP peptides, PACAP38 and PACAP27, a shorter form corresponding to the N-terminal 27 amino acids of PACAP38.

GENE FUNCTION

Freson et al. (2004) described 2 related patients with a partial trisomy 18p, 3 copies of the PACAP gene, and elevated PACAP plasma concentrations. In addition to severe mental retardation, the patients had a bleeding tendency with mild thrombocytopenia, and their fibroblasts showed increased PACAP mRNA levels. They also had increased basal cAMP levels in platelets and fibroblasts, providing a basis for the observed reduction in platelet aggregation. Freson et al. (2004) found that megakaryocyte-specific transgenic overexpression of PACAP in mice correspondingly increased PACAP release from platelets, reduced platelet activation, and prolonged the tail bleeding time. Inhibition of PACAP by an antagonist or antibody enhanced the collagen-induced aggregation of normal human platelets, and an increased platelet sensitivity toward collagen was found in PACAP knockout mice. Freson et al. (2004) concluded that PACAP modulates platelet function and that their patients represented the first reported hemostatic defect associated with PACAP overexpression.

Mercer et al. (2004) found that cultured neural stem cells isolated from the lateral ventricle wall of adult mice expressed Pac1 (102981) 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. Pacap stimulated cultured neural stem cells to form multipotent neurospheres with the capacity to generate both neuronal and glial cells. Intracerebroventricular infusion of Pacap increased cell proliferation in the ventricular zone of the lateral ventricle and the dentate gyrus of the hippocampus. Mercer et al. (2004) concluded that PACAP, through PAC1, is a potent mediator of adult neural stem cell proliferation.

GENE STRUCTURE

Hosoya et al. (1992) determined that the ADCYAP1 gene contains 5 exons and spans about 7 kb. The putative promoter region contains CRE and TRE elements and a GHF1 (173110)-binding site, but no apparent TATA, CCAAT, or GC boxes.

MAPPING

On the basis of DNA isolated from a mouse A9 microcell hybrid clone containing a single human chromosome, Hosoya et al. (1992) assigned the PACAP gene to chromosome 18; it was regionalized to 18p11 by in situ hybridization.

MOLECULAR GENETICS

Perez-Jurado and Francke (1993) described a dinucleotide repeat polymorphism in the 3-prime untranslated region of the PACAP gene.

EVOLUTION

Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, Dorus et al. (2004) examined the evolution of genes involved in diverse aspects of nervous system biology. These genes, including ADCYAP1, displayed significantly higher rates of protein evolution in primates than in rodents. This trend was most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution was most prominent in the lineage leading from ancestral primates to humans. Dorus et al. (2004) concluded that the phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development.

ANIMAL MODEL

PACAP has been conserved remarkably during evolution and is widely expressed in the mammalian brain. In Drosophila, mutation of the PACAP homolog results in behavioral defects, including impaired olfactory-associated learning and changes in ethanol sensitivity. Hashimoto et al. (2001) reported the generation of mice lacking the PACAP gene. These mice were born in the expected mammalian ratios but had a high early-mortality rate. The surviving adult PACAP -/- mice displayed remarkable behavioral changes: hyperactive and explosive jumping behaviors in an open field, increased exploratory behavior, and less anxiety in the elevated-plus maze, emergence, and novel-object tests. Analysis of the brains of PACAP -/- mice revealed that the serotonin metabolite 5-hydroxyindoleacetic acid was slightly decreased in the cortex and striatum compared with wildtype mice. Thus, PACAP plays a previously uncharacterized role in the regulation of psychomotor behaviors.

The adrenal gland is important for homeostatic responses to metabolic stress: hypoglycemia stimulates the splanchnic nerve, epinephrine is released from adrenomedullary chromaffin cells, and compensatory glucogenesis ensues. Acetylcholine is the primary neurotransmitter mediating catecholamine secretion from the adrenal medulla. Hamelink et al. (2002) added to the accumulating evidence that a secretin-related neuropeptide also may function as a transmitter at the adrenomedullary synapse. Costaining with highly specific antibodies against PACAP revealed that it is found in nerve endings at all mouse adrenomedullary cholinergic synapses. Mice with a targeted deletion of the PACAP gene had otherwise normal cholinergic innervation and morphology of the adrenal medulla, normal adrenal catecholamine and blood glucose levels, and an intact initial catecholamine secretory response to insulin-induced hypoglycemia. However, insulin-induced hypoglycemia was more profound and longer lasting in PACAP knockouts, and was associated with a dose-related lethality absent in wildtype mice. Failure of Pacap-deficient mice to counterregulate adequately plasma glucose levels could be accounted for by impaired long-term secretion of epinephrine, secondary to a lack of induction of tyrosine hydroxylase, normally occurring after insulin hypoglycemia in wildtype mice, and a consequent depletion of adrenomedullary epinephrine stores. Thus, Hamelink et al. (2002) concluded that PACAP is needed to couple epinephrine biosynthesis to secretion during metabolic stress. PACAP appears to function as an 'emergency response' cotransmitter in the sympathoadrenal axis, where the primary secretory response is controlled by a classic neurotransmitter but sustained under paraphysiologic conditions by a neuropeptide.

REFERENCES

1. Dorus, S.; Vallender, E. J.; Evans, P. D.; Anderson, J. R.; Gilbert, S. L.; Mahowald, M.; Wyckoff, G. J.; Malcom, C. M.; Lahn, B. T. :

Accelerated evolution of nervous system genes in the origin of Homo sapiens. Cell 119: 1027-1040, 2004.
PubMed ID : 15620360

2. 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. :

The pituitary adenylate cyclase-activating polypeptide is a physiological inhibitor of platelet activation. J. Clin. Invest. 113: 905-912, 2004.
PubMed ID : 15067323

3. Hamelink, C.; Tjurmina, O.; Damadzic, R.; Young, W. S.; Weihe, E.; Lee, H.-W.; Eiden, L. E. :

Pituitary adenylate cyclase-activating polypeptide is a sympathoadrenal neurotransmitter involved in catecholamine regulation and glucohomeostasis. Proc. Nat. Acad. Sci. 99: 461-466, 2002.
PubMed ID : 11756684

4. Hashimoto, H.; Shintani, N.; Tanaka, K.; Mori, W.; Hirose, M.; Matsuda, T.; Sakaue, M.; Miyazaki, J.; Niwa, H.; Tashiro, F.; Yamamoto, K.; Koga, K.; Tomimoto, S.; Kunugi, A.; Suetake, S.; Baba, A. :

Altered psychomotor behaviors in mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP). Proc. Nat. Acad. Sci. 98: 13355-13360, 2001.
PubMed ID : 11687615

5. Hosoya, M.; Kimura, C.; Ogi, K.; Ohkubo, S.; Miyamoto, Y.; Kugoh, H.; Shimizu, M.; Onda, H.; Oshimura, M.; Arimura, A.; Fujino, M. :

Structure of the human pituitary adenylate cyclase activating polypeptide (PACAP) gene. Biochim. Biophys. Acta 1129: 199-206, 1992.
PubMed ID : 1730060

6. 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 ID : 15048918

7. Perez-Jurado, L. A.; Francke, U. :

Dinucleotide repeat polymorphism at the human pituitary adenylate cyclase activating polypeptide (PACAP) gene. Hum. Molec. Genet. 2: 827 only, 1993.
PubMed ID : 8353512

CONTRIBUTORS

Patricia A. Hartz - updated : 6/23/2005
Stylianos E. Antonarakis - updated : 1/10/2005
Patricia A. Hartz - updated : 6/18/2004
Marla J. F. O'Neill - updated : 5/20/2004
Victor A. McKusick - updated : 6/3/2002
Victor A. McKusick - updated : 12/14/2001

CREATION DATE

Victor A. McKusick : 7/8/1993

EDIT HISTORY

wwang : 8/3/2005
wwang : 7/21/2005
terry : 6/23/2005
mgross : 1/10/2005
mgross : 6/24/2004
terry : 6/18/2004
mgross : 6/10/2004
terry : 6/8/2004
carol : 6/8/2004
terry : 5/20/2004
cwells : 6/26/2002
terry : 6/3/2002
alopez : 12/18/2001
terry : 12/14/2001
alopez : 8/25/1998
alopez : 9/3/1997
carol : 8/31/1993
carol : 7/8/1993

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