ADCYAP1 (adenylate cyclase activating polypeptide 1 (pituitary))

2014-09-01   Terry Moody 

National Cancer Institute, Center for Cancer Research, Office of the Director, 9609 Medical Center Drive, Rm 2W130, Bethesda, Maryland 20892, USA

Identity

HGNC
LOCATION
18p11.32
IMAGE
Atlas Image
LEGEND
Structure of human prepro-PACAP. Human prepro-PACAP (1-176) is metabolized by signal proteases to generate pro-PACAP (26-176). Pro-PACAP is metabolized by pro-hormone convertases to (26-79), big PACAP-related peptide (82-129; PRP) and PACAP-38. Pro-PACAP (26-176) can be further metabolized to PRP (82-109) and PACAP-27 by other enzymes.
LEGEND
PACAP is derived from the 176 amino acid precursor protein prepro-PACAP. Initially the signal peptide (1-25) is cleaved by signal proteases to generate pro-PACAP (26-176). Pro-PACAP is metabolized by pro-hormone convertases and carboxypeptidases to (26-79), (82-129) and (132-170). The C-terminal peptides (132-170) and (132-159) are metabolized to by peptidylglycine alpha-amidating monooxygenase enzymes to PACAP-38 and PACAP-27, respectively, which have amidated C-terminals.
LOCUSID
ALIAS
PACAP

DNA/RNA

Note

The ADCYAP1 gene encodes 5 exons and is localized to chromosome 18p11 (Kimura et al., 1990). Exons 1 and 2 encode for the 5UTR and the signal peptide. Exon 3 encodes for the N-terminal of pro-PACAP upstream from PRP. PRP is encoded by Exon 4. Exon 5 encodes for the C-terminal of pro-PACAP including PACAP-27, PACAP-38 and the 3UTR (Vaudry et al., 2009).

Description

The PACAP gene which contains 7230 bases is highly conserved in nature (Sherwood et al., 2000).

Transcription

The gene transcript is 2.7 kb (Ghatei et al., 1993).

Proteins

Note

Pituitary adenylate cyclase-activating polypeptide (PACAP) was isolated from ovine hypothalamus and contains 38 amino acids. PACAP-38 elevates cAMP in rat pituitary cells in culture (Miyata et al., 1989). PACAP-27 was isolated from ovine hypothalamus and had the same N-terminal 27 amino acids as does PACAP-38 (Miyata et al., 1990). PACAP-27 has high homology with vasoactive intestinal peptide (VIP) and moderate homology with PRP. The PACAP-38 amino acid sequence is identical in mammals. PACAP has a β-turn at residues 9-12, followed by an α-helix at residues 12-14, 15-20 and 22-24 (Inooka et al., 1992).
PACAP binds with high affinity to 3 GPCR (VPAC1, VPAC2 and PAC1) which are members of the class II or class B secretin-like receptors (Harmar et al., 2012). The activated VPAC1, VPAC2 or PAC1 interacts with a stimulatory guanine nucleotide binding protein (Gs) increasing adenylylcyclase activity resulting in elevated cAMP (Arimura et al., 1992). The increased cAMP activates protein kinase (PK) A causing phosphorylation of various proteins such as CREB leading to altered gene expression (Moody et al., 2003). In addition, PAC1 interacts with Gq causing phosphatidylinositol (PI) turnover (Pisegna and Wank, 1996). The resulting metabolites inositol-1,4,5-trisphosphate and diacylglycerol increases cytosolic calcium and activates protein kinase C, respectively.

Expression

PACAP is produced in neurons within the adrenals, brain, gastrointestinal (GI) tract, pituitary and testis (Ghatei et al., 1993). Addition of PACAP to adrenal chormaffin cells causes catecholamine release (Watanabe et al., 1990). High densities of PACAP are present in the hypothalamus and PACAP as well as glutamate shift the circadian rhythm in the suprachiasmatic nucleus (Vaudry et al., 2009). In the gastrointestinal tract PACAP stimulates the secretion of saliva, gastric acid, bicarbonate and peptides leading to myorelaxation (Moody et al., 2011). In PACAP knockout mice or mice treated with PACAP(6-38) there is reduced insulin secretion after glucose challenge (Shintani et al., 2003). In pituitary cells, PACAP elevates cAMP increasing the secretion of LH, GH, PRL, ACTH and TSH (Vaudry et al., 2009). The results indicate that PACAP is present in the normal CNS and periphery.

Localisation

Prepro-PACAP is stored in dense core neurosecretory granules in cells. In cellular extracts approximately an order of magnitude more PACAP-38 is detected than PRP or PACAP-27. PACAP-38 and PACAP-27 have approximately an order of magnitude more biological activity than does PRP (Fahrenkrug, 2010). PACAP is metabolized by neutral endopeptidase and has a half life of 5 min.

Function

PACAP alters neurotransmitter release in the CNS, causes increased insulin and histamine secretion in the periphery, controls vasodilation, bronchodilation alters intestinal motility and stimulates cellular proliferation as well as differentiation (Vaudry et al., 2009).

Homology

VIP has 67% sequence homology with PACAP-27. The sequence for PACAP-38 is identical in mammals (Fahrenkrug, 2010).

Mutations

Note

Sequence mutations of PACAP-38 are rare. Numerous mutations of PAC1 have been reported including deletions, which affect PACAP binding (PAC1 short; PAC1 very short) and splice variants, which affect signal transduction (hip, hop1, hop2; Blechman and Levkowitz, 2013). SNP rs2267735 of PAC1 is associated with post-traumatic stress disorder (PTSD) in females (Ressler et al., 2011).

Implicated in

Entity name
Lung cancer
Note
PACAP-38 immunoreactivity is higher in the human lung cancer than normal lung biopsy specimens (Szanto et al., 2012). PAC1 is present in lung cancer cells and PACAP(6-38) inhibits their proliferation (Zia et al., 1995). PACAP-27 may stimulate lung cancer proliferation as a result of EGFR transactivation (Moody et al., 2012).
Entity name
Breast cancer
Note
A 19.9 kDa prepro-PACAP was detected in human breast cancer biopsy specimens (Garcia Fernandez et al., 2004). PACAP-27 stimulated and PACAP(6-38) inhibited the growth of breast cancer cells (Leyton et al., 1999).
Entity name
Colon cancer
Note
PACAP knockout mice but not wild type mice develop colitis and colorectal tumors after treatment with dextran sulfate sodium (Nemetz et al., 2008). PACAP-38 stimulates the growth of colon cancer cells (Le et al., 2002).
Entity name
Pheochromocytoma
Note
PACAP increases the cAMP after addition to PC12 adrenal pheochromocytoma cells (Watanabe et al., 1990) and causes catecholamine secretion (Taupenot et al., 1999). PACAP addition to PC12 cells increases their survival as a result of Trk receptor tyrosine kinase phosphorylation and activation of Akt (Rajagopal et al., 2004).
Entity name
Pituitary adenoma
Note
PACAP inhibits apoptosis caused by TGFβ addition to human pituitary adenoma cells (Oka et al., 1999). PAC1 receptor mRNA was present in all pituitary adenoma cells except prolactnomas (Oka et al., 1998).
Entity name
Medulloblastoma
Note
Disruption of a single copy of the PACAP gene increased medulloblastoma incidence in ptc1 mutant mice 2.5-fold (Lelievre et al., 2008).
Entity name
Diabetes
Note
ADCYAP1 stimulates insulin secretion in a glucose-dependent manner (Filipsson et al., 2001). Two SNPs g.9863G>A, G54D in exon 3, and g.12712C>G in exon 5 were found in European type 2 diabetic patients (Gu et al., 2002).
Entity name
Neuronal survival
Note
PACAP stimulates neurite outgrowth and enhances neuronal cell survival (Canonico et al., 1996). PACAP addition to rat cerebellar neurites increases cAMP and inhibits caspase-3 activity (Vaudry et al., 2009).
Entity name
Schizophrenia
Note
In PACAP knockout mice and schizophrenic patients, brain strathmin I is up-regulated (Hashimoto et al., 2007). PACAP reduces Strathmin I in animal models of schizophrenia by inhibiting the association of the DISCI-binding zinc-finger protein with DBZ (Katayama et al., 2009).

Bibliography

Pubmed IDLast YearTitleAuthors
13135971992Pituitary adenylate cyclase activating polypeptide (PACAP): discovery and current status of research.Arimura A et al
237341442013Alternative Splicing of the Pituitary Adenylate Cyclase-Activating Polypeptide Receptor PAC1: Mechanisms of Fine Tuning of Brain Activity.Blechman J et al
89934251996Activation of pituitary adenylate cyclase-activating polypeptide receptors prevents apoptotic cell death in cultured cerebellar granule cells.Canonico PL et al
198596782010VIP and PACAP.Fahrenkrug J et al
115226602001The neuropeptide pituitary adenylate cyclase-activating polypeptide and islet function.Filipsson K et al
150366512004PACAP expression and distribution in human breast cancer and healthy tissue.García-Fernández MO et al
80940911993Distribution, molecular characterization of pituitary adenylate cyclase-activating polypeptide and its precursor encoding messenger RNA in human and rat tissues.Ghatei MA et al
119680922002Genetic variation screening and association studies of the adenylate cyclase activating polypeptide 1 (ADCYAP1) gene in patients with type 2 diabetes.Gu HF et al
222890552012Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1.Harmar AJ et al
173873182007Pituitary adenylate cyclase-activating polypeptide is associated with schizophrenia.Hashimoto R et al
14838391992Pituitary adenylate cyclase activating polypeptide (PACAP) with 27 residues. Conformation determined by 1H NMR and CD spectroscopies and distance geometry in 25% methanol solution.Inooka H et al
199580952009Role of the PACAP-PAC1-DISC1 and PACAP-PAC1-stathmin1 systems in schizophrenia and bipolar disorder: novel treatment mechanisms?Katayama T et al
23022171990A novel peptide which stimulates adenylate cyclase: molecular cloning and characterization of the ovine and human cDNAs.Kimura C et al
124092232002PAC1 and PACAP expression, signaling, and effect on the growth of HCT8, human colonic tumor cells.Le SV et al
180365802008Disruption of the PACAP gene promotes medulloblastoma in ptc1 mutant mice.Lelievre V et al
105731101999PACAP(6-38) is a PACAP receptor antagonist for breast cancer cells.Leyton J et al
28033201989Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells.Miyata A et al
23832621990Isolation of a neuropeptide corresponding to the N-terminal 27 residues of the pituitary adenylate cyclase activating polypeptide with 38 residues (PACAP38).Miyata A et al
125708132003Neuropeptides as autocrine growth factors in cancer cells.Moody TW et al
211573202011VIP and PACAP: recent insights into their functions/roles in physiology and disease from molecular and genetic studies.Moody TW et al
223894262012Pituitary adenylate cyclase-activating polypeptide causes tyrosine phosphorylation of the epidermal growth factor receptor in lung cancer cells.Moody TW et al
180982892008Induction of colitis and rapid development of colorectal tumors in mice deficient in the neuropeptide PACAP.Nemetz N et al
105959201999Pituitary adenylate cyclase-activating polypeptide inhibits transforming growth factor-beta1-induced apoptosis in a human pituitary adenoma cell line.Oka H et al
86633631996Cloning and characterization of the signal transduction of four splice variants of the human pituitary adenylate cyclase activating polypeptide receptor. Evidence for dual coupling to adenylate cyclase and phospholipase C.Pisegna JR et al
152822672004Transactivation of Trk neurotrophin receptors by G-protein-coupled receptor ligands occurs on intracellular membranes.Rajagopal R et al
213504822011Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor.Ressler KJ et al
111330672000The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily.Sherwood NM et al
146072622003Functional roles of the neuropeptide PACAP in brain and pancreas.Shintani N et al
226485112012PACAP immunoreactivity in human malignant tumor samples and cardiac diseases.Szanto Z et al
105671981999Time-dependent effects of the neuropeptide PACAP on catecholamine secretion : stimulation and desensitization.Taupenot L et al
198054772009Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery.Vaudry D et al
21751771990Adrenal pheochromocytoma PC12h cells respond to pituitary adenylate cyclase activating polypeptide.Watanabe T et al
75855251995Pituitary adenylate cyclase activating peptide receptors regulate the growth of non-small cell lung cancer cells.Zia F et al

Other Information

Locus ID:

NCBI: 116
MIM: 102980
HGNC: 241
Ensembl: ENSG00000141433

Variants:

dbSNP: 116
ClinVar: 116
TCGA: ENSG00000141433
COSMIC: ADCYAP1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000141433ENST00000450565P18509
ENSG00000141433ENST00000579794P18509

Expression (GTEx)

0
5
10
15
20

Pathways

PathwaySourceExternal ID
Insulin secretionKEGGhsa04911
Renin secretionKEGGhsa04924
Renin secretionKEGGko04924
Signal TransductionREACTOMER-HSA-162582
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Activation of TRKA receptorsREACTOMER-HSA-187015
NGF-independant TRKA activationREACTOMER-HSA-187024
Signaling by GPCRREACTOMER-HSA-372790
GPCR ligand bindingREACTOMER-HSA-500792
Class B/2 (Secretin family receptors)REACTOMER-HSA-373080
Glucagon-type ligand receptorsREACTOMER-HSA-420092
GPCR downstream signalingREACTOMER-HSA-388396
G alpha (s) signalling eventsREACTOMER-HSA-418555

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
213504822011Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor.270
200721162010Differential association of circadian genes with mood disorders: CRY1 and NPAS2 are associated with unipolar major depression and CLOCK and VIP with bipolar disorder.91
173873182007Pituitary adenylate cyclase-activating polypeptide is associated with schizophrenia.51
174708062007Solution structure and mutational analysis of pituitary adenylate cyclase-activating polypeptide binding to the extracellular domain of PAC1-RS.50
235170782013VIP and PACAP: neuropeptide modulators of CNS inflammation, injury, and repair.47
205546942010Circadian clock gene polymorphisms in alcohol use disorders and alcohol consumption.45
194701682009NPAS2 and PER2 are linked to risk factors of the metabolic syndrome.42
201336342010Apurinic/apyrimidinic endonuclease APE1 is required for PACAP-induced neuroprotection against global cerebral ischemia.38
190860532009Identification of new putative susceptibility genes for several psychiatric disorders by association analysis of regulatory and non-synonymous SNPs of 306 genes involved in neurotransmission and neurodevelopment.34
235983742013Alterations in PACAP-38-like immunoreactivity in the plasma during ictal and interictal periods of migraine patients.34

Citation

Terry Moody

ADCYAP1 (adenylate cyclase activating polypeptide 1 (pituitary))

Atlas Genet Cytogenet Oncol Haematol. 2014-09-01

Online version: http://atlasgeneticsoncology.org/gene/43656/adcyap1