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).

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

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

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.

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.

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.

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).

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

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).