The human VIP gene encodes 7 exons and is localized to chromosome 6q25.2 (Fahrenkrug, 2010).

The VIP gene spans 8837 bp.

The gene transcript has 1601 bp.

Said and Mutt (1970) sequenced an acid extractable peptide from the porcine duodenum which decreased systemic arterial pressure and increased heart rate, stroke volume, mesenteric and femoral blood flow in the dog. The 27 amino acid peptide was named vasoactive intestinal peptide (VIP). VIP is metabolized (Bodner et al., 1985) from a 170 amino acid precursor protein (preproVIP). Each exon encodes a distinct domain of the preproVIP 5 untranslated regions of the mRNA (exon I); signal peptide of preproVIP (exon II); N-terminal peptide (exon III); peptide histidine methionine (PHM) (exon IV); VIP (exon V); C-terminal of preproVIP (exon VI); untranslated region of the mRNA (exon VII). VIP and PHM, which have 48% amino acid homology, are in adjacent exons and the introns surrounding these exons are highly conserved. The substrate prepro-VIP is initially metabolized by a signal protease to form the product 149 amino acid pro-VIP. Pro-VIP is metabolized by prohormone convertases to VIP-GKR (preproVIP(125-155)) and PHM-GKR (preproVIP(81-110)). The basic amino acids are cleaved by carboxypeptidase B and the G is metabolized to an amide by PAM enzymes. Thus the N-terminal of VIP and PHM is free whereas the C-terminal is amidated. VIP is structurally related to pituitary adenylate cyclase activating polypeptide (PACAP) (Arimura, 1992). VIP has a β-turn at residues 2-5 and 7-10 followed by an α-helix at residues 11-26 (Vaudry et al., 2009).
VIP binds with high affinity to 2 GPCR (VPAC1 and VPAC2) which are members of the class II or class B secretin-like receptors but not PAC1 which binds PACAP with high affinity (Harmar et al., 2012). The activated VPAC1 or VPAC2 interacts with a stimulatory guanine nucleotide binding protein (Gs) causing increased adenylylcyclase activity resulting in elevated cAMP. The increased cAMP activates protein kinase (PK) A causing phosphorylation of various proteins such as CREB leading to altered gene expression.

VIP is produced in neurons within the adrenals, brain, gastrointestinal (GI) tract, heart, pituitary and pancreas (Sundler et al., 1988). VIP addition to the adrenals causes catecholamine release (Card et al., 1988). VIP expression in the suprachiasmatic nucleus of the brain is altered by light-dark cycles (Gozes et al., 1989) suggesting that it may play a role in circadian cycles. VIP reduction in knockout mice is associated with human motility disorders (Moody et al., 2011). In the heart, VIP-containing nerve fibers are abundant in arteries but not veins and venules (Sundler et al., 1988). VIP secretion from pancreatic neurons alters enzyme and electrolyte secretion (Konturek et al., 1976). In the pituitary, VIP gene expression is regulated by estrogen leading to altered prolactin secretion (Montagne et al., 1995). VIP is present in and secreted from immune cells especially Th2 cells altering cytokine and chemokine production (Gonzalez-Rey et al., 2007). The VIP gene is in NSCLC cells and its expression is regulated in a PKC and cAMP dependent manner (Davidson et al., 1996). VIP is present in neuroblastoma and pheochromocytoma (Beinfeld et al., 1988). The results indicate that VIP is present in normal neurons and cancer cells.

PreproVIP is stored in dense core neurosecretory granules in cells. PHM, proVIP and VIP are secreted when cAMP is elevated. While VIP has potent biological activity, PHM and proVIP are also active (Fahrenkrug, 1991). In NSCLC cells, the ratio of PHM/ proVIP/VIP is 1/3/1 respectively (Moody et al., 2003). VIP is metabolized by neutral endopeptidase and has a half life of 2 min (Henning and Sawmiller, 2001).

VIP is a cotransmitter with nitric oxide and carbon monoxide of nonadrenergic, noncholinergic vascular and nonvascular smooth muscle (Said and Rattan, 2004). It is a cotransmitter with acetylcholine in exocrine glands (Fahrenkrug, 1993). VIP promotes neuronal survival (Brenneman and Eiden, 1986). VIP causes prolactin secretion from the pituitary (Reichlin, 1988) and catecholamine release from the adrenal medulla (Malhotra et al., 1988). In the immune system VIP regulates T cell traffic and proliferation (Ottaway, 1987).

VIP has 67% sequence homology with PACAP-27. The sequence for VIP is identical in the human, bovine, porcine and rat.

The VIP gene is altered in patients with idiopathic pulmonary arterial hypertension (IPAH) (Haberl et al., 2007). The 3 untranslated region in exon 7 is mutated (g.8129T>C) leading to reduced VIP serum levels and higher pulmonary artery pressure (Zhang et al., 2009).