VIP (vasoactive intestinal peptide)

2013-08-01   Terry Moody 

National Cancer Institute, Center for Cancer Research, Office of the Director, 31 Center Drive, Bldg 31, Rm 4A48, Bethesda, Maryland 20892, USA

Identity

HGNC
LOCATION
6q25.2
IMAGE
Atlas Image
LEGEND
Structure of human preproVIP. VIP is derived from the 170 amino acid precursor protein preproVIP. Initially the signal peptide (1-20) is cleaved by signal proteases to generate proVIP. ProVIP (22-170) is metabolized to (22-79), PHM (81-107), (111-122), VIP (125-152) and (156-170) by prohormone convertases. Carboxypeptidase B-like enzymes cleave basic R and K. The C-terminal of PHM and VIP is amidated when G is metabolized by peptidylglycine alpha-amidating monooxygenase (PAM) enzymes.
LOCUSID
ALIAS
PHM27

DNA/RNA

Note

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

Description

The VIP gene spans 8837 bp.

Transcription

The gene transcript has 1601 bp.

Proteins

Description

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.

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.

Localisation

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).

Function

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).

Homology

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

Mutations

Note

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).

Implicated in

Entity name
Pancreatic cancer
Note
VIPomas were described by Verner and Morrison (1958). Most of the VIPomas occur in the pancreas leading to diarrheal fluid similar to that seen in patient with cholera, hence the term pancreatic cholera of watery diarrhea, hypokalemic and achlorhydric (WDHA) has been used. The plasma VIP levels are significantly elevated in patients with VIPomas (Long et al., 1981).
Entity name
Lung cancer
Note
The VIP gene is expressed in numerous lung cancer cell lines (Davidson et al., 1996). Pro-VIP and VIP are present in lung cancer cell lines (Moody et al., 2003). VIP (10 nM) increases lung cancer colony formation which is inhibited by the VPAC1 antagonist VIPhybrid (Moody et al., 1993). High densities of VPAC1 are present in lung cancer cells (Moody and Gozes, 2007).
Entity name
Breast cancer
Note
VIP addition to breast cancer cells causes transactivation of the EGF receptor and HER2 (Valdehita et al., 2009). Addition of VIP-camptothecin conjugates causes apoptosis of breast cancer cells (Moody et al., 2007).
Entity name
Renal cell carcinoma
Note
Addition of 100 nM VIP to renal cancer cells decreases proliferation (Vacas et al., 2012). High concentrations of VIP may cause differentiation of cancer cells (Hoosein et al., 1989).
Entity name
Prostate cancer
Note
High densities of VPAC1 were detected in prostate cancer cell lines (Reubi et al., 2000).
Entity name
Colon cancer
Note
123I-VIP can be used to visualize colon cancer tumors in patients (Raderer et al., 1998).
Entity name
Diabetes
Note
Overexpression of the VIP gene in mouse pancreatic beta cells resulted in reduced blood glucose and insensitivity to glucose intolerance (Passemard et al., 2011).
Entity name
Bronchial asthma
Note
VIP nerves are absent in severely asthmatic subjects. Mice with targeted deletion of the VIP gene exhibit histopathologic features of airway inflammation (Said et al., 2010).
Entity name
Cardiomyopathy
Note
Hearts were dilated in VIP knockout mice with thinning of the left ventricular wall and increases in right ventricular and left ventricular chamber size resulting from overexpression of cardiomyophathy genes (Szema et al., 2013). VIP is a potent vasodilator and increases the heart rate (Henning and Sawmiller, 2001).

Bibliography

Pubmed IDLast YearTitleAuthors

Other Information

Locus ID:

NCBI: 7432
MIM: 192320
HGNC: 12693
Ensembl: ENSG00000146469

Variants:

dbSNP: 7432
ClinVar: 7432
TCGA: ENSG00000146469
COSMIC: VIP

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000146469ENST00000367243P01282
ENSG00000146469ENST00000367244P01282
ENSG00000146469ENST00000431366H0Y763

Expression (GTEx)

0
10
20
30
40
50
60
70
80

Pathways

PathwaySourceExternal ID
Signal TransductionREACTOMER-HSA-162582
Signaling by GPCRREACTOMER-HSA-372790
GPCR downstream signalingREACTOMER-HSA-388396
G alpha (s) signalling eventsREACTOMER-HSA-418555

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
177034122007Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes.100
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
235170782013VIP and PACAP: neuropeptide modulators of CNS inflammation, injury, and repair.47
270136762016Opening Holes in the Blanket of Inhibition: Localized Lateral Disinhibition by VIP Interneurons.46
186033062008Antimicrobial activity of neuropeptides against a range of micro-organisms from skin, oral, respiratory and gastrointestinal tract sites.45
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
259215962015Suprachiasmatic neuron numbers and rest-activity circadian rhythms in older humans.40
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
203989082010Comprehensive copy number variant (CNV) analysis of neuronal pathways genes in psychiatric disorders identifies rare variants within patients.32

Citation

Terry Moody

VIP (vasoactive intestinal peptide)

Atlas Genet Cytogenet Oncol Haematol. 2013-08-01

Online version: http://atlasgeneticsoncology.org/gene/44215/css/template-card.css