VIP

Summary

VIP (vasoactive intestinal peptide, HGNC:12693) is a protein-coding gene on chromosome 6q25.2, encoding VIP peptides (P01282). VIP is a neuropeptide involved in a diverse array of physiological processes through activating the PACAP subfamily of class B1 G protein-coupled receptors: VIP receptor 1 (VPR1) and VIP receptor 2 (VPR2).

The protein encoded by this gene belongs to the glucagon family. It stimulates myocardial contractility, causes vasodilation, increases glycogenolysis, lowers arterial blood pressure and relaxes the smooth muscle of trachea, stomach and gall bladder. The protein also acts as an antimicrobial peptide with antibacterial and antifungal activity. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified.

Source: NCBI Gene 7432 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Asperger syndrome (Limited, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 16 total
• GTEx eGene: eQTL in 22 tissues, sQTL in 1 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.47 (unconstrained)
• MANE Select transcript: NM_003381
• Interaction hub: 1,818 STRING partners (top 9% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12693
Approved symbol	VIP
Name	vasoactive intestinal peptide
Location	6q25.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000146469
Ensembl biotype	protein_coding
OMIM	192320
Entrez	7432

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 9 protein_coding

MANE Select: ENST00000367244

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 3: 1

ENST00000367244, ENST00000367243, ENST00000431366, ENST00000897583, ENST00000897584, ENST00000897585, ENST00000897586, ENST00000897587, ENST00001141112

RefSeq mRNA: 2 — MANE Select: NM_003381 NM_003381, NM_194435

CCDS: CCDS5240, CCDS5241

Canonical transcript exons

ENST00000367244 — 7 exons

Exon	Start	End
ENSE00000976009	152754166	152754288
ENSE00000976010	152755269	152755373
ENSE00000976011	152756134	152756265
ENSE00000976012	152757096	152757184
ENSE00001443920	152752168	152752284
ENSE00003841961	152750797	152750959
ENSE00003848106	152758910	152759760

Expression profiles

Bgee: expression breadth ubiquitous, 182 present calls, max score 96.53.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.1087 / max 347.7204, expressed in 113 samples.

Highest expression (Bgee): vermiform appendix, rectum, caecum, primordial germ cell in gonad, muscle layer of sigmoid colon.

Genetic regulation across tissues (GTEx eQTL / sQTL)

VIP is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 22 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 23 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Thyroid	eqtl	2.1e-15	-0.56	6:152682293:A:G
Adipose Subcutaneous	eqtl	1.7e-13	-0.50	6:152700864:G:A
Nerve Tibial	eqtl	2.9e-11	+0.26	6:152727853:G:A
Testis	eqtl	4.4e-11	+0.51	6:152731792:G:C
Heart Left Ventricle	eqtl	1.8e-09	-0.52	6:152683048:G:T
Lung	eqtl	1.1e-06	-0.54	6:152715767:A:C
Breast Mammary Tissue	eqtl	1.5e-06	-0.46	6:152714673:G:A
Brain Cerebellar Hemisphere	eqtl	4.1e-06	+0.49	6:152786635:C:G
Artery Tibial	eqtl	1.5e-05	-0.37	6:152700864:G:A
Esophagus Mucosa	eqtl	2.3e-05	+0.22	6:152727853:G:A
Spleen	eqtl	3.8e-05	+0.27	6:152727853:G:A
Muscle Skeletal	eqtl	1.9e-04	-0.43	6:152683048:G:T
Adipose Visceral Omentum	eqtl	3.4e-04	-0.39	6:152704985:C:T
Brain Cerebellum	eqtl	3.5e-04	+0.49	6:152787986:G:A
Skin Not Sun Exposed Suprapubic	eqtl	6.3e-04	+0.19	6:152731792:G:C
Heart Atrial Appendage	eqtl	7.7e-04	-0.45	6:152683048:G:T
Minor Salivary Gland	eqtl	8.1e-03	-0.80	6:152609620:G:A
Pituitary	eqtl	8.2e-03	-0.57	6:153392352:T:TA
Prostate	eqtl	1.7e-02	-0.72	6:152712893:TTATA:T
Skin Sun Exposed Lower leg	eqtl	2.0e-02	+0.62	6:152396255:T:G

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
70653	1.1087	113

Top tissues by expression

showing 100 of 282 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
vermiform appendix	UBERON:0001154	96.53	gold quality
rectum	UBERON:0001052	96.20	gold quality
caecum	UBERON:0001153	95.99	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.68	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.24	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.68	gold quality
mucosa of stomach	UBERON:0001199	88.97	gold quality
endothelial cell	CL:0000115	88.59	gold quality
transverse colon	UBERON:0001157	87.30	gold quality
cingulate cortex	UBERON:0003027	85.65	gold quality
anterior cingulate cortex	UBERON:0009835	85.46	gold quality
lower esophagus muscularis layer	UBERON:0035833	85.32	gold quality
lower esophagus	UBERON:0013473	85.10	gold quality
sigmoid colon	UBERON:0001159	84.87	gold quality
prefrontal cortex	UBERON:0000451	84.59	gold quality
large intestine	UBERON:0000059	84.29	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	84.17	gold quality
colon	UBERON:0001155	84.12	gold quality
intestine	UBERON:0000160	83.38	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	83.17	gold quality
colonic epithelium	UBERON:0000397	83.04	gold quality
right frontal lobe	UBERON:0002810	82.34	gold quality
Brodmann (1909) area 10	UBERON:0013541	82.06	gold quality
small intestine Peyer’s patch	UBERON:0003454	81.76	gold quality
amygdala	UBERON:0001876	81.49	gold quality
Brodmann (1909) area 9	UBERON:0013540	80.89	gold quality
frontal cortex	UBERON:0001870	80.33	gold quality
neocortex	UBERON:0001950	80.31	gold quality
small intestine	UBERON:0002108	80.16	gold quality
mucosa of transverse colon	UBERON:0004991	79.77	gold quality
smooth muscle tissue	UBERON:0001135	79.10	gold quality
fundus of stomach	UBERON:0001160	78.61	gold quality
cerebral cortex	UBERON:0000956	78.59	gold quality
spleen	UBERON:0002106	76.76	gold quality
islet of Langerhans	UBERON:0000006	76.41	gold quality
frontal pole	UBERON:0002795	76.33	gold quality
temporal lobe	UBERON:0001871	75.88	gold quality
Ammon’s horn	UBERON:0001954	75.35	gold quality
primary visual cortex	UBERON:0002436	75.09	gold quality
apex of heart	UBERON:0002098	74.54	gold quality
telencephalon	UBERON:0001893	73.71	gold quality
occipital lobe	UBERON:0002021	72.17	gold quality
gall bladder	UBERON:0002110	72.15	gold quality
duodenum	UBERON:0002114	71.95	gold quality
forebrain	UBERON:0001890	71.30	gold quality
body of stomach	UBERON:0001161	70.76	gold quality
esophagus	UBERON:0001043	70.35	gold quality
pancreas	UBERON:0001264	70.23	gold quality
right lung	UBERON:0002167	70.18	gold quality
stomach	UBERON:0000945	70.15	gold quality
upper lobe of left lung	UBERON:0008952	70.02	gold quality
orbitofrontal cortex	UBERON:0004167	69.97	gold quality
superior frontal gyrus	UBERON:0002661	69.79	gold quality
omental fat pad	UBERON:0010414	69.42	gold quality
heart left ventricle	UBERON:0002084	69.36	gold quality
peritoneum	UBERON:0002358	69.34	gold quality
brain	UBERON:0000955	69.24	gold quality
upper lobe of lung	UBERON:0008948	69.16	gold quality
Brodmann (1909) area 46	UBERON:0006483	68.96	gold quality
hypothalamus	UBERON:0001898	68.81	gold quality
central nervous system	UBERON:0001017	68.79	gold quality
body of pancreas	UBERON:0001150	68.51	gold quality
cardiac ventricle	UBERON:0002082	68.45	gold quality
entorhinal cortex	UBERON:0002728	68.45	gold quality
adipose tissue of abdominal region	UBERON:0007808	67.95	gold quality
middle temporal gyrus	UBERON:0002771	67.88	gold quality
Brodmann (1909) area 23	UBERON:0013554	67.76	gold quality
caudate nucleus	UBERON:0001873	66.43	gold quality
body of uterus	UBERON:0009853	66.37	gold quality
right lobe of thyroid gland	UBERON:0001119	65.86	gold quality
right atrium auricular region	UBERON:0006631	65.86	gold quality
left lobe of thyroid gland	UBERON:0001120	65.31	gold quality
right hemisphere of cerebellum	UBERON:0014890	65.27	gold quality
heart	UBERON:0000948	65.18	gold quality
right adrenal gland	UBERON:0001233	65.12	gold quality
postcentral gyrus	UBERON:0002581	65.06	gold quality
right adrenal gland cortex	UBERON:0035827	64.85	gold quality
parietal lobe	UBERON:0001872	64.64	gold quality
cardiac atrium	UBERON:0002081	64.49	gold quality
thyroid gland	UBERON:0002046	64.46	gold quality
cerebellar hemisphere	UBERON:0002245	64.38	gold quality
cerebellar cortex	UBERON:0002129	64.16	gold quality
left uterine tube	UBERON:0001303	63.30	gold quality
subcutaneous adipose tissue	UBERON:0002190	62.98	gold quality
gastrocnemius	UBERON:0001388	62.52	gold quality
cerebellum	UBERON:0002037	62.25	gold quality
lower esophagus mucosa	UBERON:0035834	62.21	gold quality
lung	UBERON:0002048	61.81	gold quality
endocervix	UBERON:0000458	61.60	gold quality
muscle of leg	UBERON:0001383	61.49	gold quality
left coronary artery	UBERON:0001626	61.31	gold quality
metanephros cortex	UBERON:0010533	61.22	gold quality
CA1 field of hippocampus	UBERON:0003881	61.12	gold quality
putamen	UBERON:0001874	60.79	gold quality
anatomical system	UBERON:0000467	60.72	gold quality
left adrenal gland cortex	UBERON:0035825	60.64	gold quality
nucleus accumbens	UBERON:0001882	60.48	gold quality
multicellular organism	UBERON:0000468	60.39	gold quality
material anatomical entity	UBERON:0000465	60.37	gold quality
right lobe of liver	UBERON:0001114	60.26	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-HCAD-25	yes	1882.14
E-HCAD-30	no	204.63
E-ANND-3	no	2.40

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Appendix	tissue	146.8	high
Frontal cortex	tissue	81.6
Colon	tissue	67.6	high
Rectum	tissue	57.6	high
Small intestine	tissue	43.0	high
Smooth muscle	tissue	38.8	low
Cerebral cortex	tissue	19.7	not detected
Motor cortex	tissue	19.7
Hippocampal formation	tissue	19.1
Entorhinal cortex	tissue	19.1
Prefrontal cortex	tissue	18.4
Retrosplenial and cingulate cortex	tissue	17.0
Insular cortex	tissue	16.4
Duodenum	tissue	15.6	high
Temporal cortex	tissue	15.6
Retrosplenial cortex	tissue	14.9
Occipital cortex	tissue	14.9
Somatosensory cortex	tissue	14.0
Adrenal gland	tissue	11.5	medium
Amygdala	tissue	9.7
Vagina	tissue	8.2	low
Pancreas	tissue	7.8	medium
Caudate putamen	tissue	7.0
Periaqueductal gray	tissue	5.2
Hippocampus	tissue	4.7	not detected
Olfactory bulb	tissue	4.5
Postcentral gyrus	tissue	4.2
Esophagus	tissue	4.0	low
Gallbladder	tissue	3.5	medium
Spleen	tissue	2.9	not detected
Corpus callosum	tissue	2.6
Hypothalamus	tissue	2.3
Cerebellum	tissue	2.2	medium
Septum	tissue	2.2
Basal ganglia	tissue	1.7	low
Ventral forebrain	tissue	1.7
Tongue	tissue	1.5
Heart muscle	tissue	1.4	medium
Putamen	tissue	1.4
Midbrain	tissue	1.4
Adipose tissue	tissue	1.3	not detected
Skeletal muscle	tissue	1.3	medium
Medulla oblongata	tissue	1.3
Lung	tissue	1.3	low
Stomach 1	tissue	1.2	medium
Pons	tissue	1.2
Substantia nigra	tissue	1.2
Spinal cord	tissue	1.1
Retina	tissue	0.9
Endometrium 1	tissue	0.9	medium
Thalamus	tissue	0.8
Superior colliculi	tissue	0.8
Cervix	tissue	0.7	low
Pituitary gland	tissue	0.6
Testis	tissue	0.6	medium
Nucleus accumbens	tissue	0.6
Thyroid gland	tissue	0.6	medium
Liver	tissue	0.6	medium
Breast	tissue	0.5	medium
Seminal vesicle	tissue	0.5	low

Brain sub-regions (HPA Brain Atlas): detected in 292; highest nTPM — Median raphe nucleus (78.0), Cerebellar nuclei (64.2), Cerebellar white matter (57.7), Supraoptic nucleus (51.9), Dorsal funiculus (white matter) (51.2).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, CEBPB, CEBPD, CEBPG, CREB1, FOS, FOSB, FOSL1, FOSL2, JUN, JUNB, JUND, NFKB, NR4A2, POU1F1, POU2F2, REST, SMAD3, SMAD4, SP1, SPI1, STAT1, STAT3

miRNA regulators (miRDB)

Targeting VIP by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 85 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-128-3P	99.95	71.17	2484

Functional genomics

gnomAD constraint: pLI 8.71e-06, LOEUF 1.47, missense Z 0.26 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000367244 — one region, missense o/e 1.05.

Literature-anchored findings (GeneRIF, showing 40)

• Besides their presence and functions in the gut and the brain VIP and PACAP have distinct physiological roles in the genital tract. (PMID:11713978)
• Circulating VIP in fulminant hepatic failure seems to reflect hemodynamic changes in the systemic rather than in the cerebral circulation. (PMID:11884208)
• mRNA of this peptide and immunoreactivity are decreased in a fetal alcohol syndrome model. (PMID:12220738)
• Vasoactive intestinal peptide (VIP) inhibits the proliferation of bone marrow progenitors through the VPAC1 receptor. (PMID:12225791)
• VIP modulation of neural crest differentiation is mediated via VPAC1 and high expression of VPAC1 induces differentiation in and decreases tumorigenicity of neuroblastoma cells. (PMID:12409228)
• Atopic dermatitis patients’ VIP levels were elevated not only in the skin but also in the serum, suggesting that increased serum levels in might be involved in its pathogenesis. (PMID:12670727)
• VIP has a role in downregulating interferon gamma in the inflammatory response in the central nervous system (PMID:12754213)
• We report here a repressor element, similar to the canonical restrictive element-1 (RE-1), located within the first non-coding exon of the human VIP gene. Endogenous RE-1 silencer factor regulates VIP gene expression in neuroblastic and non-neuronal cells (PMID:15009665)
• VIP induces neuroendocrine differentiation in prostate cancer cells and has proangiogenic potential (PMID:15093699)
• Thus, in human skin, VIP-mediated vasodilation includes a NO-dependent component that could not be explained by H1- and H2-receptor activation. (PMID:15155712)
• the central part of VIP, at least between Phe(6) and Tyr(22), interacts with the N-terminal ectodomain of the hVPAC1 receptor (PMID:15247290)
• Results show that the combination of different amino terminal and intracellular loop 3 splicing variants in the PAC1 receptor dictates the ability of agonists, including PACAP and VIP, to activate signaling pathways. (PMID:16226889)
• VIP and PACAP stimulate the synthesis and release of adrenomedullary catecholamines, and all three subtypes of PACAP/VIP Rs mediate this effect, PAC(1)-Rs being coupled to AC, VPAC(1)-Rs to both AC and PLC, and VPAC(2)-Rs only to PLC. (PMID:16697281)
• antiapoptotic signaling pathways activated by vasoactive intestinal polypeptide, epidermal growth factor, and phosphatidylinositol 3-kinase in prostate cancer cells converge on BAD (PMID:16728406)
• HNF4alpha, CREM, HNF1alpha, and C/EBPalpha have roles in transcriptional regulation of the glucose-6-phosphatase gene by cAMP/vasoactive intestinal peptide in the intestine (PMID:16893891)
• Has protective effects against human bronchial epithelial cell damage. (PMID:16965837)
• Study investigated the relevance of genetic alterations in VIP to the development of idiopathic pulmonary arterial hypertension; analysis of VIP gene from 10 patients could not be correlated with the disease. (PMID:17003842)
• SP, CGRP and VIP may play important roles in the pathophysiological mechanism of vasomotor rhinitis. (PMID:17087112)
• VIP has an inhibitory effect on IL-1beta-induced ICAM-1 expression in serous fibroblasts, which may be associated with NF-kappaB activity (PMID:17275031)
• This paper reviews the role of VIP in neurodevelopment, its known involvement in neurodevelopmental disorders and proposes ways in which VIP might be of therapeutic value. (PMID:17430171)
• The aim of this review is (1) to update our knowledge of the cellular and molecular events relevant to VIP function in the immune system; and (2) to gather recent data that support its role as a type 2 cytokine. (PMID:17430175)
• inflammation is associated with a differential expression of VIP and nNOS neuronal subpopulations within the two major enteric plexi, likely due to phenotypic switch in Crohn disease (PMID:17466601)
• a proangiogenic potential of vasoactive intestinal peptide in breast cancer. (PMID:17683807)
• in trophic and anti-inflammatory VIP effects occurs in areas exhibiting a very marked inflammation (PMID:17804556)
• Structural studies provide a detailed molecular understanding of the VIP-VPAC1 receptor interaction. (PMID:17885205)
• The abnormal excretion of hormonal factors is closely related to gallstone formation (PMID:18234640)
• VIP and PACAP levels were decreased in anterior vaginal wall of stress urinary incontinence and pelvic organ prolapse patients,they may participate in the pathophysiology of these diseases. (PMID:18351280)
• VIP(Vasoactive intestinal peptide) expression was decreased in Rhematoid Arthritis (RA) synovial fibroblasts (FLS) compared with Osteoarthritis(OA) FLS;in RA FLS, VPAC2 (VIP receptor type 2) mediates the antiinflammatory effects of VIP (PMID:18383383)
• study demonstrated the role of corneal endothelial cell VIP in maintaining the expression level of a corneal endothelial differentiation marker, N-cadherin, and the hexagonal cell shape (PMID:18441300)
• The antimicrobial peptide, VIP is a neuropeptide with activity against a range of microorganisms from skin, oral, respiratory and gastrointestinal tract sites. (PMID:18603306)
• VIP acts in an autocrine fashion via VPAC1 to inhibit megakaryocyte proliferation and induce proplatelet formation (PMID:18663606)
• These results suggest that the VIP-mediated wound repair of HBECs is associated with activation of CREB via PKA and ERK dependent pathway. (PMID:19136032)
• VIP secreting Neuroblastic tumors are usually associated with differentiation; they can also secondarily arise from a high-risk tumor upon treatment (PMID:19143025)
• secretin stimulates VIP release from postganglionic neurons in the gastric myenteric plexus. (PMID:19239625)
• There is evidence that VIP is a neurotransmitter in the vaginal epithelium. The anterior vaginal wall has a more important role than the posterior wall. Change of VIP is related to age in pelvic organ prolapse patients. (PMID:19272598)
• Reduction in the quantitative sudomotor axon reflex test and VIP expression in the sweat glands might be involved in the dyshidrosis of PD patients. (PMID:19476518)
• Investigated the correlation between VIP gene variants and idiopathic pulmonary arterial hypertension (IPAH) in Chinese population. The VIP gene variant g.8129T–>C may be one of the risk factors in the pathogenesis of IPAH. (PMID:19508420)
• The VIP level of the nasal septum in the perennial allergic rhinitis patients was higher than that in the normal controls. (PMID:19685709)
• Results suggest for the first time a role of FOS in PACAP-induced VIP gene expression in human NB-1 neuroblastoma cells. (PMID:19712974)
• Relaxation reaction via VIP nerves and contraction via SP nerves might be involved in regulation of enteric nervous system in the normal human PS. (PMID:19950799)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	vip	ENSDARG00000078247
danio_rerio	vipb	ENSDARG00000079443
mus_musculus	Vip	ENSMUSG00000019772
rattus_norvegicus	Vip	ENSRNOG00000018808

Paralogs (2): GHRH (ENSG00000118702), ADCYAP1 (ENSG00000141433)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:98933) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 15 distinct phenotype terms.

Mouse phenotype (MP)	Records
heart right ventricle hypertrophy	1
abnormal pulmonary artery morphology	1
seminiferous tubule degeneration	1
lung inflammation	1
premature death	1
decreased circulating testosterone level	1
decreased circulating follicle stimulating hormone level	1
pulmonary hypertension	1
abnormal lung vasculature morphology	1
decreased seminal vesicle weight	1
increased right ventricle systolic pressure	1
decreased testes secretion	1
shortened circadian behavior period	1
arrhythmic circadian behavior persistence	1
abnormal circadian behavior phase	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Heloderma suspectum cinctum	C6EVG2	100.0%	Diamond
Sus scrofa	P01284	100.0%	Diamond
Heloderma suspectum	P04203	100.0%	Diamond
Heloderma horridum horridum	P0DJ94	100.0%	Diamond
Oryctolagus cuniculus	P32649	100.0%	Diamond
Meleagris gallopavo	P45644	97.5%	Diamond
Gallus gallus	P48143	97.5%	Diamond
Cavia porcellus	P04566	96.3%	Diamond
Bos taurus	P81401	96.3%	Diamond
Oncorhynchus nerka	P41585	91.3%	Diamond
Cyprinus carpio	P42692	91.1%	Diamond
Pelophylax ridibundus	Q09169	78.3%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
LINC02840	ncRNA	105378065
SYNE1	protein-coding	23345
MYCT1	protein-coding	80177

Protein

Protein identifiers

VIP peptides — P01282 (reviewed: P01282)

All UniProt accessions (2): P01282, H0Y763

UniProt curated annotations — full annotation on UniProt →

Function. VIP is a neuropeptide involved in a diverse array of physiological processes through activating the PACAP subfamily of class B1 G protein-coupled receptors: VIP receptor 1 (VPR1) and VIP receptor 2 (VPR2). Abundantly expressed throughout the CNS and peripheral nervous systems where they primarily exert neuroprotective and immune modulatory roles. Also causes vasodilation, lowers arterial blood pressure, stimulates myocardial contractility, increases glycogenolysis and relaxes the smooth muscle of trachea, stomach and gall bladder. Bioactive forms that cause vasodilation. PHM-27 is a potent agonist of the calcitonin receptor CALCR, with similar efficacy as calcitonin. Bioactive forms that cause vasodilation.

Subcellular location. Secreted.

Similarity. Belongs to the glucagon family.

Isoforms (2)

UniProt ID	Names	Canonical?
P01282-1	1	yes
P01282-2	2

RefSeq proteins (2): NP_003372, NP_919416 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000532	Glucagon_GIP_secretin_VIP	Domain
IPR046963	VIP/GHRH-like	Family

Pfam: PF00123

UniProt features (14 total): sequence conflict 3, peptide 3, modified residue 3, propeptide 2, signal peptide 1, helix 1, splice variant 1

Structure

Experimental structures (PDB)

5 structures by resolution:

PDB	Title	Method	Resolution (Å)
8E3Z	Cryo-EM structure of the VPAC1R-VIP-Gs complex	ELECTRON MICROSCOPY	2.7
9P93	Cryo-EM structure of the PAC1sR-VIP-Gs complex	ELECTRON MICROSCOPY	3.2
9P92	Cryo-EM structure of the PAC1nR-VIP-Gs complex	ELECTRON MICROSCOPY	3.8
2RRH	NMR structure of vasoactive intestinal peptide in Methanol	SOLUTION NMR
2RRI	NMR structure of vasoactive intestinal peptide in DPC Micelle	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01282-F1	67.73	0.16

Antibody-complex structures (SAbDab)

3 antibodies co-crystallized with this protein: 8E3Z, 9P92, 9P93

Human Protein Atlas

Protein class: Predicted secreted proteins, Predicted intracellular proteins, Cancer-related genes, Candidate cancer biomarkers

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): endoplasmic reticulum

Antibody reliability (HPA): IH supported · IF approved

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3)

Type	Positions
Phosphoserine	76
Methionine amide	107
Asparagine amide	152

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 7; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

7 pathways:

ID	Pathway	Evidence
R-HSA-418555	G alpha (s) signalling events	curated
R-HSA-420092	Glucagon-type ligand receptors	curated
R-HSA-373080	Class B/2 (Secretin family receptors)	—
R-HSA-388396	GPCR downstream signalling	—
R-HSA-500792	GPCR ligand binding	—
R-HSA-162582	Signal Transduction	—
R-HSA-372790	Signaling by GPCR	—

MSigDB gene sets: 195 (showing top): ATF_B, MODULE_92, REACTOME_GLUCAGON_TYPE_LIGAND_RECEPTORS, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, NKX25_02, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, STAT3_01, AAAYRNCTG_UNKNOWN, GOBP_CELL_CELL_SIGNALING, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION

GO Biological Process (10): G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), body fluid secretion (GO:0007589), positive regulation of cell population proliferation (GO:0008284), regulation of protein localization (GO:0032880), positive regulation of protein catabolic process (GO:0045732), epinephrine secretion (GO:0048242), mRNA stabilization (GO:0048255), prolactin secretion (GO:0070459), positive regulation of cAMP/PKA signal transduction (GO:0141163)

GO Molecular Function (6): hormone activity (GO:0005179), neuropeptide hormone activity (GO:0005184), type 1 vasoactive intestinal polypeptide receptor binding (GO:0031891), type 2 vasoactive intestinal polypeptide receptor binding (GO:0031892), peptide hormone receptor binding (GO:0051428), protein binding (GO:0005515)

GO Cellular Component (2): extracellular region (GO:0005576), neuron projection (GO:0043005)

Reactome top-level categories

5 top-level categories:

Category	Pathways
Signaling by GPCR	2
GPCR downstream signalling	1
Class B/2 (Secretin family receptors)	1
Signal Transduction	1
GPCR ligand binding	1

GO top-level categories

32 GO namespaces:

Category	Terms
vasoactive intestinal polypeptide receptor binding	2
G protein-coupled receptor activity	1
signal transduction	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
secretion	1
regulation of body fluid levels	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
intracellular protein localization	1
regulation of localization	1
positive regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
catecholamine secretion	1
regulation of mRNA stability	1
RNA stabilization	1
negative regulation of mRNA catabolic process	1
protein secretion	1
peptide hormone secretion	1
cAMP/PKA signal transduction	1
regulation of cAMP/PKA signal transduction	1
positive regulation of intracellular signal transduction	1
receptor ligand activity	1
hormone activity	1
neuropeptide activity	1
hormone receptor binding	1
binding	1
cellular anatomical structure	1
plasma membrane bounded cell projection	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 19 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO term	NS	Evidence
adenylate cyclase-activating G protein-coupled receptor signaling pathway	BP	direct assay
positive regulation of protein catabolic process	BP	direct assay
regulation of protein localization	BP	direct assay
hormone activity	MF	direct assay
neuropeptide hormone activity	MF	direct assay
peptide hormone receptor binding	MF	physical interaction
type 1 vasoactive intestinal polypeptide receptor binding	MF	direct assay
type 2 vasoactive intestinal polypeptide receptor binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,818 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VIP	SCT	P09683	978
VIP	VIPR1	P32241	970
VIP	VIPR2	P41587	959
VIP	TAC1	P20366	938
VIP	ADCYAP1R1	P41586	921
VIP	GHRH	P01286	895
VIP	SST	P01166	886
VIP	NPY	P01303	881
VIP	GRP	P07491	856
VIP	GAST	P01350	855
VIP	GIP	P09681	850
VIP	PPY	P01298	831
VIP	GAL	P22466	822
VIP	POMC	P01189	797
VIP	CRH	P06850	792

IntAct

Human interaction partners of VIP in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

8 partners by confidence:

Partner	Interaction type	MIscore	Records
SGTA	physical association	0.560	3
DPP4	cleavage reaction	0.440	2
FAP	cleavage reaction	0.440	2
MEOX2	physical association	0.370	1
LRP2	association	0.350	1
VGF	association	0.350	1
VHL	association	0.350	1
UBQLN4	physical association	0.000	1

BioGRID (21 interactions; top human partners by supporting records): ACTBL2 (Affinity Capture-MS; 2 records), LRP2 (Affinity Capture-MS; 2 records), PPP2R2D (Affinity Capture-MS; 2 records), PXDN (Affinity Capture-MS; 2 records), C16orf72 (Negative Genetic), CTNNA3 (Two-hybrid), KLHL13 (Affinity Capture-MS), KLHL9 (Affinity Capture-MS), MEOX2 (Two-hybrid), MEP1A (Biochemical Activity), MGST1 (Two-hybrid), NMU (Affinity Capture-MS), SGTA (Two-hybrid), UBQLN2 (Two-hybrid), UBQLN4 (Two-hybrid)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
VIP	up-regulates	VIPR1	binding

Ligand–receptor pairs (CellPhoneDB) (4)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

4 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
SCTR	ligand	Signaling by Vasoactive Intestinal Peptide
VIPR2	ligand	Signaling by Vasoactive Intestinal Peptide
ADCYAP1R1	ligand	Signaling by Vasoactive Intestinal Peptide
VIPR1	ligand	Signaling by Vasoactive Intestinal Peptide

Disease & clinical

Genetic variants

Variant evidence for VIP: 16 ClinVar records (0 pathogenic / likely pathogenic); 5 GWAS associations.

ClinVar

16 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	11
Likely benign	2
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 29 predictions of 403):

Position(s)	Effect	Δscore	Sites
6:152750960	donor_loss	1.0000	2
6:152754289–152754290	donor_loss	1.0000	5
6:152755261	acceptor_gain	1.0000
6:152755267–152755268	acceptor_loss	1.0000	6
6:152755370	donor_gain	1.0000
6:152755374–152755375	donor_loss	1.0000	4
6:152756124	acceptor_gain	1.0000
6:152757086	acceptor_gain	1.0000
6:152750961	donor_loss	0.9900	2
6:152752166–152752167	acceptor_loss	0.9900	6

AlphaMissense

306 missense substitutions predicted likely pathogenic (of 1,114 scored), across 66 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D127	8	0.975	0.989
F130	8	0.973	0.998
H125	8	0.958	0.982
F86	8	0.930	0.989
H81	8	0.922	0.968
D83	8	0.866	0.935
D132	7	0.957	0.983
R80	7	0.903	0.981
R155	7	0.880	0.979
M141	7	0.824	0.952
D89	7	0.677	0.801
R138	6	0.953	0.996
R124	6	0.951	0.994
T131	6	0.951	0.996
A142	6	0.946	0.997
K139	6	0.923	0.982
K123	6	0.915	0.981
L147	6	0.871	0.998
K154	6	0.845	0.949
K145	6	0.798	0.928

HPA cancer prognostics

RNA cancer specificity: Group enriched (Colon Adenocarcinoma, Pancreatic Adenocarcinoma, Rectum Adenocarcinoma, Stomach Adenocarcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Pancreatic Adenocarcinoma (validation)	unfavorable	0.000669

Disease associations

OMIM: gene MIM:192320 | disease phenotypes:

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
Asperger syndrome	Limited	Autosomal dominant

Mondo (1): (MONDO:0005259)

GWAS associations

5 associations:

Study	Trait	p-value
GCST007565_29	Morning person	4e-33
GCST007576_158	Chronotype	4e-33
GCST007576_380	Chronotype	9e-30
GCST003429_53	Morning vs. evening chronotype	4e-11
GCST005951_99	Body mass index	1e-9

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0008328	chronotype measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5737 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

11 measured of 13 human assays (68 total across all organisms); most potent 11 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CAS_150828-75-4	KI	3.4 nM
PACAP-VIP	KI	8 nM
[Ser9,Tyr13]VIP	KI	15 nM
PACAP(1-27)	EC50	20.6 nM
VIP [D-Met17]	KI	29.5 nM
[Tyr13]VIP	KI	40 nM
[Ser9]VIP	KI	50 nM
VIP-PACAP	KI	100 nM
SR 147778	KI	1000 nM
CHEMBL5285378	IC50	19200 nM
CHEBI:80954	IC50	19800 nM

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Copper	affects cotreatment, decreases expression, affects binding, increases expression	2
fenamic acid	increases expression, increases reaction	1
8-((4-chlorophenyl)thio)cyclic-3’,5’-AMP	increases expression	1
sodium arsenite	increases expression	1
nickel chloride	affects cotreatment, increases secretion, increases expression	1
N-(2-aminoethyl)-5-isoquinolinesulfonamide	decreases reaction, increases expression	1
5-nitro-2-(3-phenylpropylamino)benzoic acid	increases expression, increases reaction	1
N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide	decreases reaction, increases expression	1
jinfukang	affects cotreatment, decreases expression	1
NSC 689534	affects binding, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Cyclic AMP	affects binding, increases abundance	1
Aspirin	increases expression	1
Atrazine	decreases expression	1
Bromocriptine	decreases reaction, increases expression	1
Cadmium	increases abundance, increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Curcumin	decreases reaction, increases activity, increases expression	1
Doxorubicin	decreases expression	1
Progesterone	increases abundance	1
Silver	increases expression	1
Tretinoin	decreases expression	1
Cyclosporine	decreases methylation	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	increases abundance, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1019022	Binding	Binding affinity to vasoactive intestinal peptide	Bioactive Prenylhydroquinone Sulfates and a Novel C 31 Furanoterpene Alcohol Sulfate from the Marine Sponge, Ircinia Sp. — *J Nat Prod*

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for VIP across ~30M SureChEMBL compounds — explore on Sugi Predict.