Affinage

VIP

VIP peptides · UniProt P01282

Length
170 aa
Mass
19.2 kDa
Annotated
2026-06-11
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VIP is a vagally-regulated neuropeptide that acts as a neurotransmitter, neuromodulator, and secretagog, signaling through two class B G protein-coupled receptors, VPAC1 and VPAC2, that couple to adenylyl cyclase to raise intracellular cAMP (PMID:2698176, PMID:12529932). It is co-encoded with the related peptide PHI/PHM on a 7-exon gene and processed from a common precursor whose products are co-localized and co-released in approximately equimolar amounts upon vagal stimulation (PMID:3548423, PMID:1851524). Downstream of receptor binding, VIP engages cAMP/PKA signaling spatially organized by AKAP scaffolds to control ryanodine-receptor-dependent Ca²⁺ transients and outward currents in smooth muscle (PMID:16571863), and in different contexts recruits parallel Ca²⁺/PLC and nitric oxide/cGMP pathways alongside co-transmitter NO in enteric neurons (PMID:15320758, PMID:15921770). In the brain, VIP is expressed by a defined class of cortical interneurons that disinhibit pyramidal cells and facilitate network activity (PMID:31081950, PMID:26961109), and VIP/VPAC2 signaling synchronizes suprachiasmatic-nucleus pacemaker neurons to sustain circadian and metabolic rhythms, a function dependent on mTOR within VIP neurons (PMID:18032467, PMID:29555746, PMID:32536240). At mucosal surfaces, food-activated enteric VIP neurons signal to ILC3s through VIPR2 to bidirectionally tune IL-22 production and epithelial barrier defense, and through VIPR1/Erk1–2–c-Fos drive epithelial fucosylation that shapes the microbiota (PMID:32050257, PMID:31873294, PMID:36150396). VIP is broadly anti-inflammatory, inhibiting pro-inflammatory transcription factors (NFκB, CREB, AP-1, IRF-1) and cytokine production in macrophages and T cells while promoting IL-10 (PMID:12090463). Its transcription is directly activated by the orphan nuclear receptor Nurr1 in midbrain dopaminergic neurons, where VIP supports neuronal survival (PMID:16999955). Genetic deletion of VIP causes airway hyperresponsiveness with inflammation that is reversed by VIP replacement, establishing endogenous VIP as a component of anti-asthma defense (PMID:16782752).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1985 Medium

    Established that VIP and the related peptide PHM derive from a single larger precursor, raising the question of how one gene generates multiple bioactive peptides and how processing varies by tissue.

    Evidence Radioimmunoassay, gel chromatography, and reduction experiments on human VIP-omas

    PMID:3840886

    Open questions at the time
    • Precursor processing enzymes not identified
    • Mechanism controlling tissue-specific VIP/PHM ratios unresolved
  2. 1986 Medium

    Defined the human VIP gene as encoding both VIP and PHM-27 and detected unspliced transcripts in a tumor, introducing RNA-processing-level regulation of VIP expression.

    Evidence Gene isolation, chemical sequencing, and RNA analysis of a VIP-producing buccal tumor

    PMID:3748844

    Open questions at the time
    • Intron retention observed in a single tumor
    • Physiological significance of unspliced transcript unknown
  3. 1987 High

    Showed that VIP and PHI are co-released in equimolar amounts upon vagal stimulation with additive secretory effects, establishing them as functional co-transmitters under cholinergic control.

    Evidence Immunohistochemistry, isolated perfused pig pancreas with electrical nerve stimulation, radioimmunoassay

    PMID:3548423

    Open questions at the time
    • Receptor mediating co-transmitter effects not defined here
    • Generalization beyond pancreas not addressed
  4. 1989 Medium

    Consolidated VIP as a neurotransmitter/secretagog acting through receptor-mediated adenylyl cyclase activation and mapped its 7-exon gene with each exon encoding a functional domain.

    Evidence Review integrating gene cloning, exon mapping, receptor binding, and cAMP assays

    PMID:2698176

    Open questions at the time
    • Distinct receptor subtypes not yet resolved
    • Non-cAMP signaling not characterized
  5. 1991 High

    Confirmed gene structure showing VIP and PHI co-encoded on the same mRNA with no differential splicing, and demonstrated pharmacological heterogeneity between CNS and immune VIP receptors.

    Evidence Mouse genomic cloning with RNase H mapping; competitive radioligand displacement on spinal cord versus lymphoid cells

    PMID:1647246 PMID:1851524

    Open questions at the time
    • Molecular identity of receptor subtypes underlying pharmacological differences not established
    • Functional consequences of receptor heterogeneity unaddressed
  6. 1994 Medium

    Demonstrated that lymphocytes produce VIP and regulate its receptors, with VPAC2 inducible by TCR stimulation and VIP, suggesting an autocrine/paracrine immune signaling loop.

    Evidence RT-PCR and Southern blot for VIP and receptor mRNA in T and B lymphocyte subpopulations

    PMID:8190917 PMID:8784257

    Open questions at the time
    • Functional consequences of lymphocyte-derived VIP not tested
    • Single method/lab evidence for receptor autoregulation
  7. 1997 Medium

    Linked a specific VIP receptor (VIP-1/VPAC1) coupled to adenylyl cyclase to cancer cell proliferation, and demonstrated evolutionary conservation of VIP receptor–cAMP coupling.

    Evidence Receptor expression analysis with cAMP/thymidine assays in pancreatic carcinoma cells; goldfish receptor heterologous expression in COS-7

    PMID:9038250 PMID:9108448

    Open questions at the time
    • Receptor subtype assignment based on pharmacology, not direct cloning in human cells
    • In vivo relevance to tumor growth not shown
  8. 2000 Medium

    Extended VIP signaling beyond cAMP, showing receptor-dependent regulation of NO/cGMP in keratinocytes and cAMP-mediated suppression of macrophage TGF-β1, distinguishing VIP from PACAP downstream wiring.

    Evidence Receptor expression, cAMP/cGMP/NO measurements, proliferation assays; LPS-stimulated macrophage cytokine and mRNA analysis with pathway inhibitors

    PMID:10808055 PMID:10858492

    Open questions at the time
    • Differential signaling of the SNV analog mechanistically unexplained
    • Single-lab cell-line systems
  9. 2002 High

    Resolved the molecular pharmacology of VPAC1 and VPAC2, mapping ligand-interaction domains and demonstrating receptor desensitization/internalization, and defined VIP's anti-inflammatory program at the transcription-factor level.

    Evidence Site-directed mutagenesis, receptor chimeras, radioligand and cAMP assays; macrophage/T-cell transcription-factor reporter and EMSA assays

    PMID:12090463 PMID:12529932

    Open questions at the time
    • Structural basis of receptor activation not solved
    • Cell-type-specific differences in transcription-factor targeting unresolved
  10. 2006 High

    Dissected the proximal signaling of VIP-induced smooth muscle relaxation (cAMP/PKA/AKAP/ryanodine receptor), identified Nurr1 as a direct transcriptional activator of VIP supporting dopaminergic survival, and showed endogenous VIP defends against airway hyperresponsiveness.

    Evidence Ca²⁺ imaging and patch-clamp with pathway inhibitors; promoter reporter and Nurr1 knockout with survival assay; VIP-knockout mice with methacholine challenge and rescue

    PMID:16571863 PMID:16782752 PMID:16999955

    Open questions at the time
    • Tissue-specificity of AKAP-anchored PKA signaling not generalized
    • Whether VIP loss contributes to human asthma not addressed
  11. 2007 High

    Established VIP/VPAC2 signaling as essential for SCN neuronal synchronization driving circadian and metabolic rhythms.

    Evidence VIP- and VPAC2-knockout mice with metabolic monitoring and behavioral recording under varying light conditions

    PMID:18032467

    Open questions at the time
    • Intracellular pathway linking VPAC2 to clock gene expression not defined here
  12. 2010 Medium

    Expanded VIP signaling to neuronal plasticity (cAMP/PKA enhancement of NMDA currents), nuclear/extranuclear receptor compartmentalization, and an autocrine/intracrine loop in cancer cells.

    Evidence Hippocampal patch-clamp with receptor pharmacology; subcellular fractionation and cAMP assay in breast cancer cells

    PMID:20414742 PMID:20691743

    Open questions at the time
    • Functional role of nuclear VPAC1 unresolved
    • Mechanism of intracrine VIP delivery to nuclear receptors unknown
  13. 2011 High

    Revealed that VPAC1 and VPAC2 exert opposing effects on mucosal inflammation, with VPAC1/PKA driving colitis severity, refining VIP's net immune role as receptor-dependent.

    Evidence VPAC1- and VPAC2-knockout mice in DSS colitis with PKA inhibitor rescue and inflammatory marker quantification

    PMID:21295288

    Open questions at the time
    • Cellular targets of opposing receptor signals not pinpointed
    • Reconciliation with anti-inflammatory VIP effects context-dependent
  14. 2018 High

    Identified mTOR within VIP neurons as a molecular requirement for SCN circadian synchrony and olfactory sensory responses, providing an intracellular effector for VIP-neuron function.

    Evidence Conditional mTOR knockout in VIP-expressing cells with behavioral, SCN imaging, and olfactory readouts

    PMID:29555746

    Open questions at the time
    • Link between mTOR and VIP peptide release not established
    • Mechanism of mTOR activation by odor in VIP neurons unclear
  15. 2020 High

    Defined the enteric VIP–ILC3 circuit as a feeding-gated rheostat of innate immunity and lipid absorption, and established VIP interneurons as critical nodes in cortical and Rett-syndrome pathophysiology.

    Evidence In vivo chemogenetics, conditional ablation, ILC3-specific VIPR2 knockout, cytokine/histology; conditional Mecp2 deletion in VIP interneurons; caspase ablation of SCN VIP neurons

    PMID:32050257 PMID:32343226 PMID:32536240

    Open questions at the time
    • Reconciliation of opposing VIPR2 effects on IL-22 across studies context-dependent
    • Downstream effectors of VIP-interneuron dysfunction in Rett model not fully mapped
  16. 2022 High

    Demonstrated that enteric VIP neurons control epithelial α1,2-fucosylation via VIPR1/Erk1–2–c-Fos, linking neuronal VIP output to microbiota composition and liver disease susceptibility.

    Evidence Vagotomy, chemogenetics, enteric neuron–organoid coculture, transcriptomics, pathway inhibitors in mice

    PMID:36150396

    Open questions at the time
    • Whether fut2 induction is direct or relayed through other epithelial signals unresolved
    • Human relevance of the VIP–fucosylation axis not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How VIP-precursor processing, receptor subtype selection (VPAC1 vs VPAC2), and downstream pathway choice (cAMP/PKA vs Ca²⁺/PLC vs NO/cGMP) are integrated to produce opposing context-dependent outcomes in immunity and inflammation remains unresolved.
  • No unifying model reconciling pro- and anti-inflammatory VIP actions
  • Structural basis of biased receptor signaling not determined
  • Tissue determinants of differential precursor processing unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005576 extracellular region 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-9909396 Circadian clock 3
Partners
NURR1PHIVIPR1VIPR2VPAC1VPAC2

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 Food intake activates enteric VIP-producing neurons whose projections in the lamina propria contact ILC3s expressing VIPR2 (VPAC2); VIP-VIPR2 signaling inhibits IL-22 production by ILC3s, reduces antimicrobial peptide secretion from epithelial cells, and increases expression of lipid-binding proteins and transporters, thereby enhancing lipid absorption at the cost of innate immune protection. In vivo chemogenetics, conditional neuron ablation, ILC3-specific receptor knockout, cytokine measurements, histology in mice Nature High 32050257
2019 Intestinal ILC3s express VIPR2 at high levels; VIP activation of VIPR2 on ILC3s markedly enhances IL-22 production and epithelial barrier function in a circadian/food-intake-dependent manner, and VIPR2 deficiency impairs IL-22 production and increases susceptibility to inflammation-induced gut injury. Flow cytometry, cytokine ELISA, VIPR2-knockout mice, gut injury models Nature immunology High 31873294
2022 Enteric VIP neurons activate fut2 expression (α1,2-fucosylation) in intestinal epithelial cells via the VIPR1 receptor through the Erk1/2–c-Fos signaling pathway, shaping gut microbiota composition and susceptibility to alcohol-associated liver disease. Subdiaphragmatic vagotomy, chemogenetics, enteric neuron–intestinal organoid coculture, transcriptomics, signaling pathway inhibitors Cell host & microbe High 36150396
1989 VIP exerts its biological effects via receptor-mediated activation of adenylyl cyclase, increasing intracellular cAMP, and acts as a neurotransmitter, neuromodulator, and secretagog; it is encoded by a 7-exon gene in humans where each exon encodes a distinct functional domain of the precursor protein. Molecular biology (gene cloning, exon mapping), receptor binding assays, cAMP measurements, immunocytochemistry Molecular neurobiology Medium 2698176
2002 VIP signals through two G protein-coupled receptors, VPAC1 and VPAC2, which activate adenylyl cyclase (cAMP pathway); receptor–ligand interaction domains were identified by site-directed mutagenesis and receptor chimera construction; receptors undergo desensitization, internalization, and phosphorylation upon VIP binding. Site-directed mutagenesis, receptor chimeras, radioligand binding, cAMP assays, receptor internalization assays Receptors & channels High 12529932
2002 In activated macrophages, VIP inhibits production of pro-inflammatory cytokines/chemokines and nitric oxide, and stimulates IL-10 production, through effects on transcription factors NFκB, CREB, c-Jun, JunB, and IRF-1 via VPAC1/VPAC2 receptors; in T cells, VIP inhibits FasL expression through NFκB, NFAT, and Egr2/3, promoting Th2 cell survival. Cell culture, cytokine ELISA, transcription factor assays (EMSA, reporter), receptor-specific agonists/antagonists Critical reviews in oral biology and medicine Medium 12090463
1987 VIP and PHI are co-encoded in the same precursor, co-localized in the same nerve fibers, co-released in approximately equimolar amounts upon vagal stimulation from pig pancreatic neurons, and have additive effects on exocrine pancreatic secretion of fluid and bicarbonate; co-release is blocked by hexamethonium and mimicked by cholinergic agonists. Immunohistochemistry, isolated perfused pig pancreas, electrical nerve stimulation, radioimmunoassay, gel chromatography The American journal of physiology High 3548423
1991 The mouse VIP gene contains 7 exons spanning 8 kb; both VIP and PHI coding sequences are present on the same mRNA with no evidence of differential splicing to produce separate transcripts; two polyadenylation sites in exon 7 give rise to a prominent 1700-base mRNA and a rare 1000-base species. Genomic cloning, Southern blot, S1 nuclease protection, RNase H-directed digestion with specific oligonucleotides Brain research. Molecular brain research High 1851524
1986 The human VIP gene contains exons encoding both VIP and PHM-27 (a related peptide); in a VIP-producing buccal tumor, a major transcript retains intron sequences, suggesting VIP gene expression is regulated at the RNA processing level. Gene isolation with synthetic oligonucleotide probes, chemical nucleotide sequencing, RNA analysis Peptides Medium 3748844
1985 VIP and PHM are co-produced from a common larger precursor in VIP-secreting tumors, but post-translational processing differs between tissues, resulting in variable VIP/PHM ratios (0.5–8.5); two larger molecular forms containing both VIP and PHM immunoreactivity were identified by gel chromatography. Radioimmunoassay, gel chromatography, protein denaturation/reduction experiments on human VIP-omas Peptides Medium 3840886
2006 Mice with targeted deletion of the VIP gene spontaneously develop airway hyperresponsiveness to methacholine and increased peribronchiolar/perivascular inflammatory infiltrates with elevated cytokines in BAL fluid; intraperitoneal VIP administration over 2 weeks virtually eliminated airway hyperresponsiveness and reduced inflammation, demonstrating that endogenous VIP is a component of anti-asthma defense mechanisms. VIP gene knockout mice, methacholine challenge, ELISA for cytokines, histology, VIP replacement therapy American journal of physiology. Lung cellular and molecular physiology High 16782752
2004 VIP and NO are co-transmitters in myenteric neurons co-innervating gastrointestinal smooth muscle; at the presynaptic level, VIP induces NO release from isolated myenteric ganglia and NO facilitates VIP release; at the postsynaptic level, VIP acts via VPAC receptors/cAMP and also induces smooth muscle NO production, with VIP and NO operating as parallel co-transmitters on adenylyl cyclase/cAMP and guanylate cyclase/cGMP pathways respectively. Isolated myenteric ganglia, isolated smooth muscle cells, pharmacological dissection with specific inhibitors, cAMP/cGMP measurements Current pharmaceutical design Medium 15320758
2006 VIP is a transcriptional target of the orphan nuclear receptor Nurr1; Nurr1 directly transactivates the VIP promoter through Nurr1-responsive cis elements; loss of Nurr1 function in vivo reduces VIP mRNA levels in the developing midbrain; VIP mediates dopaminergic cell survival when cells are challenged with paraquat. Differential display, promoter reporter assay, VIP mRNA/protein measurements in Nurr1-regulated dopaminergic cell line, Nurr1 knockout in vivo (in situ hybridization), paraquat survival assay Experimental neurology High 16999955
2006 VIP regulates localized Ca²⁺ transients (Ca²⁺ puffs) and spontaneous transient outward currents (STOCs) in colonic smooth muscle cells via adenylyl cyclase-dependent cAMP synthesis and PKA-dependent regulation of ryanodine receptor channels; disruption of AKAP associations blocks VIP effects, indicating spatial organization of PKA signaling is required. Confocal Ca²⁺ imaging, patch-clamp electrophysiology, pharmacological inhibitors (MDL-12330A, AKAP St-Ht31 inhibitory peptide, ryanodine receptor blockers), dibutyryl-cAMP application American journal of physiology. Cell physiology High 16571863
2018 mTOR signaling in VIP neurons regulates circadian clock synchrony: conditional knockout of mTOR in VIP-expressing cells impairs synchronization among SCN neurons and produces erratic circadian behavior; mTOR in VIP neurons of the olfactory bulb is activated by odor stimuli and is required for odor-evoked c-Fos responses and normal olfactory sensitivity. Cre-LoxP conditional knockout, wheel-running behavior, SCN cellular imaging, c-Fos immunostaining, olfactory sensitivity testing Proceedings of the National Academy of Sciences of the United States of America High 29555746
2007 VIP and VPAC2 signaling are critical for intercellular synchronization among SCN neurons and for circadian rhythms of metabolism and feeding; mice lacking either VIP or VPAC2 receptor show advanced and dampened daily metabolic/feeding rhythms, and VPAC2-knockout mice have globally reduced metabolic rate. VIP-knockout and VPAC2-knockout mice, metabolic monitoring, wheel-running behavior, light/dark and constant light conditions American journal of physiology. Regulatory, integrative and comparative physiology High 18032467
2020 Ablation of VIP neurons in the adult SCN shortens circadian period and reduces duration of daily activity, and severely dampens corticosterone rhythms, but does not abolish locomotor rhythmicity; in contrast, neonatal SCN VIP neuron ablation dramatically reduces circadian gene expression and mimics global Vip deletion, indicating developmental and adult roles of VIP neurons in SCN function differ. Caspase3-mediated cell ablation in VIP-Cre mice, wheel-running, corticosterone measurements, SCN PER2::LUC bioluminescence recording Journal of biological rhythms High 32536240
2017 ErbB4 deletion specifically from VIP interneurons during development alters VIP interneuron activity patterns, severely dysregulates cortical temporal organization and state dependence, reduces cortical responses to sensory stimuli, and impairs sensory learning; phenotypes emerge during adolescence. Conditional ErbB4 knockout in VIP interneurons, in vivo electrophysiology, sensory learning behavioral assays Neuron High 28817803
2019 Nicotine directly depolarizes and excites VIP interneurons via nicotinic acetylcholine receptors; chemogenetic inhibition of VIP neurons prevents nicotine's indirect excitatory effects on pyramidal neurons, establishing that VIP cells disinhibit pyramidal cells (by inhibiting other interneurons) in auditory cortex. Whole-cell patch-clamp recordings in vitro, receptor antagonists, DREADD-mediated chemogenetic inhibition of VIP neurons Synapse (New York, N.Y.) High 31081950
2016 VIP+ interneurons exert a state-independent facilitation of neocortical network activity; pharmacogenetic blockade of VIP+ cell output reduces network activity during locomotion, non-locomotion, anesthesia, and visual stimulation. VIP+ cell activity correlates most strongly with mean population activity of nearby excitatory neurons. In vivo Ca²⁺ imaging (two-photon), pharmacogenetic (DREADD) blockade of VIP+ neurons in mouse visual cortex Journal of neurophysiology High 26961109
2003 VIP stimulates astrocytes to secrete neuroprotective proteins including activity-dependent neurotrophic factor (ADNF) and activity-dependent neuroprotective protein (ADNP); ADNP was discovered as a glial-cell mediator of VIP-induced neuroprotection. The lipophilic VIP analog SNV was identified as retaining neuroprotective activity with improved stability. Embryonic neuron cultures, astrocyte conditioned medium experiments, protein identification, analog synthesis and activity assays Journal of molecular neuroscience : MN Medium 14501014
2000 VIP and its potent lipophilic analog SNV promote human keratinocyte proliferation via VPAC1 and VPAC2 receptors; keratinocytes express PACAP but not VIP mRNA, suggesting paracrine VIP and autocrine PACAP signaling; VIP and SNV increase nitric oxide and cGMP levels in keratinocytes; SNV does not elevate cAMP (unlike VIP), indicating differential downstream signaling. RT-PCR for receptor expression, cell proliferation assays, cAMP and cGMP measurements, NO measurement FEBS letters Medium 10858492
1991 A VIP antagonist (neurotensin-VIP hybrid) binds VIP receptors on spinal cord cells with 10-fold higher affinity than VIP itself, but requires 1000-fold higher concentrations to displace VIP from lymphoid cell receptors, demonstrating pharmacological heterogeneity between central nervous system and immune VIP receptors. Competitive radioligand displacement assays on spinal cord cells and lymphoid cells Brain research Medium 1647246
1997 VIP-1 receptor expression is required for VIP-stimulated growth of pancreatic adenocarcinoma cells; VIP (100 pM) stimulates Capan-2 cell growth via VIP-1 receptors coupled to adenylyl cyclase (half-maximal cAMP increase at 0.5–5 nM VIP); secretin (1 μM but not 1 nM) also stimulates cAMP, consistent with VIP-1 receptor pharmacology. RT-PCR/Southern blot for receptor expression, cAMP assay, [³H]-thymidine incorporation for cell growth Cancer research Medium 9108448
2000 VIP and PACAP inhibit LPS-stimulated TGF-β1 production in macrophages (both Raw 264.7 cell line and peritoneal macrophages) by reducing TGF-β1 steady-state mRNA levels; this effect is mediated through VPAC1, VPAC2, and PAC1 receptors; VIP acts primarily through the cAMP pathway while PACAP activates both cAMP and protein kinase C pathways. LPS stimulation of macrophages, cytokine ELISA, Northern/RT-PCR for mRNA levels, receptor-selective pharmacology, PKC/PKA pathway inhibitors, in vivo VIP administration Journal of neuroimmunology Medium 10808055
2005 In prostate LNCaP cells, VIP induces c-fos mRNA and protein expression via a Ca²⁺-dependent mechanism; VIP elevates intracellular Ca²⁺, and chelation with BAPTA/AM abolishes c-fos induction; VIP stimulates VEGF mRNA and protein expression through both cAMP/PKA and Ca²⁺ pathways, and AP-1 binding (c-Fos/c-Jun) is required for VEGF upregulation; VIP also induces neuroendocrine differentiation (neurite outgrowth) partially dependent on Ca²⁺. RT-PCR, Western blot, fura-2 Ca²⁺ imaging, BAPTA/AM chelation, specific kinase inhibitors (H89, curcumin), real-time RT-PCR Biochimica et biophysica acta Medium 15921770
2011 VPAC1 receptor signaling mediates VIP enhancement of DSS-induced colitis severity; in VPAC2-knockout mice, colitis is worsened and suppression of VPAC1 signals with PKA inhibitors reduces clinical severity and tissue levels of IL-6, IL-1β, and MMP-9, demonstrating that VPAC1 and VPAC2 have opposing roles in regulating mucosal inflammation. VPAC1-KO and VPAC2-KO mice, DSS-induced colitis model, myeloperoxidase assay, cytokine/MMP ELISA, PKA inhibitor treatment Cellular immunology High 21295288
2010 VIP/PACAP activation of VPAC1/VPAC2 receptors in CA1 pyramidal cells increases evoked NMDA currents via the cAMP/PKA pathway, while PACAP activation of PAC1 receptors enhances NMDA receptor function through a PLC/PKC/Pyk2/Src signaling pathway. Electrophysiology (patch-clamp) in hippocampal neurons, pharmacological receptor and pathway dissection Journal of molecular neuroscience : MN Medium 20414742
1997 A goldfish full-length VIP receptor expressed in COS-7 cells couples to cAMP production in response to VIP and PACAP; VIP shows higher potency than PACAP (EC50 of VIP = 1 nM), establishing conserved receptor-G protein coupling across vertebrate evolution. cDNA cloning, heterologous expression in COS-7 cells, cAMP radioimmunoassay, competitive peptide concentration-response General and comparative endocrinology Medium 9038250
2010 VPAC1 receptor is localized to the nuclear fraction of human breast cancer cells, while VPAC2 receptor is extranuclear; both receptors are functional as shown by VIP-stimulated cAMP production from both plasma membrane and nuclear fractions; VIP also increases its own intracellular and extracellular levels, suggesting an autocrine/intracrine regulatory loop. Subcellular fractionation, Western blot, cAMP assay on nuclear and membrane fractions, immunohistochemistry of breast tumor samples Peptides Medium 20691743
1994 VIP-R2 (VPAC2) expression in T lymphocytes is inducible upon TCR/CD3 stimulation, whereas VIP-R1 (VPAC1) is constitutively expressed; VIP itself can induce VIP-R2 gene expression in T cells in the absence of additional stimuli, suggesting positive autoregulation of the VIP signaling axis in lymphocytes. RT-PCR for VIP-R1 and VIP-R2 mRNA in unstimulated and TCR-stimulated lymphocyte subpopulations Journal of neuroimmunology Medium 8784257
1994 VIP mRNA is expressed in rat T and B lymphocytes (thymocytes, splenic and lymph node T and B cells) and in a T-T hybridoma, establishing that immune cells themselves can produce VIP as a potential autocrine/paracrine cytokine. RT-PCR, Southern blot analysis, confirmed by size comparison with cortical VIP cDNA Regulatory peptides Medium 8190917
2020 Loss of MeCP2 specifically from VIP interneurons replicates key neural and behavioral phenotypes of global Mecp2 loss of function (Rett Syndrome model), identifying VIP interneuron dysfunction as a key pathophysiological node. Conditional Mecp2 knockout restricted to VIP interneurons, behavioral phenotyping, neural circuit analysis eLife Medium 32343226

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1980 Vasoactive intestinal polypeptide (VIP) in mouse and rat brain: an immunocytochemical study. Brain research 380 6986955
2020 Feeding-dependent VIP neuron-ILC3 circuit regulates the intestinal barrier. Nature 295 32050257
1989 VIP: molecular biology and neurobiological function. Molecular neurobiology 240 2698176
1993 Type I receptors for PACAP (a neuropeptide even more important than VIP?). Biochimica et biophysica acta 207 8218337
2019 The neuropeptide VIP confers anticipatory mucosal immunity by regulating ILC3 activity. Nature immunology 198 31873294
2016 Bacterial Vegetative Insecticidal Proteins (Vip) from Entomopathogenic Bacteria. Microbiology and molecular biology reviews : MMBR 193 26935135
2013 VIP and PACAP: neuropeptide modulators of CNS inflammation, injury, and repair. British journal of pharmacology 178 23517078
2002 VPAC receptors for VIP and PACAP. Receptors & channels 163 12529932
2005 Neuroprotective potential of three neuropeptides PACAP, VIP and PHI. Pharmacological reports : PR 151 15985713
2002 Molecular pharmacology and structure of VPAC Receptors for VIP and PACAP. Regulatory peptides 132 12220741
2006 Salivary levels of CGRP and VIP in rhinosinusitis and migraine patients. Headache 131 16412148
2002 Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) as modulators of both innate and adaptive immunity. Critical reviews in oral biology and medicine : an official publication of the American Association of Oral Biologists 122 12090463
2017 Developmental Dysfunction of VIP Interneurons Impairs Cortical Circuits. Neuron 116 28817803
2013 Emerging neuropeptide targets in inflammation: NPY and VIP. American journal of physiology. Gastrointestinal and liver physiology 116 23538492
1999 VIP and PACAP: very important in pain? Trends in pharmacological sciences 111 10431211
1977 VIP innervation of the gallbladder. Gastroenterology 104 858483
1996 The significance of vasoactive intestinal polypeptide (VIP) in immunomodulation. Advances in neuroimmunology 102 8790778
1996 Differential expression of vasoactive intestinal peptide receptors 1 and 2 (VIP-R1 and VIP-R2) mRNA in murine lymphocytes. Journal of neuroimmunology 98 8784257
2006 VIP-PACAP system in immunity: new insights for multitarget therapy. Annals of the New York Academy of Sciences 95 16888149
2003 VIP as a trophic factor in the CNS and cancer cells. Peptides 88 12576099
2004 Interaction of NO and VIP in gastrointestinal smooth muscle relaxation. Current pharmaceutical design 81 15320758
2003 From vasoactive intestinal peptide (VIP) through activity-dependent neuroprotective protein (ADNP) to NAP: a view of neuroprotection and cell division. Journal of molecular neuroscience : MN 80 14501014
2016 VIP+ interneurons control neocortical activity across brain states. Journal of neurophysiology 77 26961109
2006 Mice lacking the VIP gene show airway hyperresponsiveness and airway inflammation, partially reversible by VIP. American journal of physiology. Lung cellular and molecular physiology 77 16782752
1994 Distribution of VIP mRNA and two distinct VIP binding sites in the developing rat brain: relation to ontogenic events. The Journal of comparative neurology 75 8201031
1996 VIP modulation of immune cell functions. Advances in neuroimmunology 73 8790783
1987 VIP and PHI in the pig pancreas: coexistence, corelease, and cooperative effects. The American journal of physiology 71 3548423
2003 Roles of vasoactive intestinal peptide (VIP) in the expression of different immune phenotypes by wild-type mice and T cell-targeted type II VIP receptor transgenic mice. Journal of immunology (Baltimore, Md. : 1950) 69 12496414
2007 Role of PACAP and VIP in astroglial functions. Peptides 68 17655978
2007 Metabolic rhythm abnormalities in mice lacking VIP-VPAC2 signaling. American journal of physiology. Regulatory, integrative and comparative physiology 66 18032467
2007 Role of VIP and PACAP in islet function. Peptides 64 17559974
2008 PACAP and VIP prevent apoptosis in schwannoma cells. Brain research 62 18835258
1987 Developmental expression of the VIP-gene in brain and intestine. Brain research 61 2441796
1991 A VIP antagonist distinguishes VIP receptors on spinal cord cells and lymphocytes. Brain research 60 1647246
1986 The receptors of the VIP family peptides (VIP, secretin, GRF, PHI, PHM, GIP, glucagon and oxyntomodulin). Specificities and identity. Peptides 60 3018707
1982 A new neuroregulator: the vasoactive intestinal peptide or VIP. Molecular and cellular endocrinology 60 6290287
1991 Characterization of the gene and messages for vasoactive intestinal polypeptide (VIP) in rat and mouse. Brain research. Molecular brain research 57 1851524
2018 Postmenopausal osteoporosis is associated with the regulation of SP, CGRP, VIP, and NPY. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 55 29807224
1984 Localisation and measurement of VIP in the genitourinary system of man and animals. Peptides 55 6382193
2022 Enteric VIP-producing neurons maintain gut microbiota homeostasis through regulating epithelium fucosylation. Cell host & microbe 54 36150396
2015 Function and Circuitry of VIP+ Interneurons in the Mouse Retina. The Journal of neuroscience : the official journal of the Society for Neuroscience 52 26224854
1994 Vasoactive intestinal peptide (VIP) mRNA expression in rat T and B lymphocytes. Regulatory peptides 52 8190917
2010 Nuclear localization of vasoactive intestinal peptide (VIP) receptors in human breast cancer. Peptides 51 20691743
2020 Evaluating Cross-resistance Between Vip and Cry Toxins of Bacillus thuringiensis. Journal of economic entomology 50 31821498
2018 Immunomodulatory Roles of PACAP and VIP: Lessons from Knockout Mice. Journal of molecular neuroscience : MN 50 30105629
2021 Vegetative Insecticidal Protein (Vip): A Potential Contender From Bacillus thuringiensis for Efficient Management of Various Detrimental Agricultural Pests. Frontiers in microbiology 49 34054756
2015 PACAP and VIP signaling in chondrogenesis and osteogenesis. Peptides 49 25701761
1997 Vasoactive intestinal peptide (VIP) stimulates in vitro growth of VIP-1 receptor-bearing human pancreatic adenocarcinoma-derived cells. Cancer research 49 9108448
1997 Molecular evolution of vertebrate VIP receptors and functional characterization of a VIP receptor from goldfish Carassius auratus. General and comparative endocrinology 47 9038250
1994 A chimeric VIP-PACAP analogue but not VIP pseudopeptides function as VIP receptor antagonists. Peptides 47 7912431
2022 Signal Transduction by VIP and PACAP Receptors. Biomedicines 46 35203615
2010 The involvement of PACAP/VIP system in the synaptic transmission in the hippocampus. Journal of molecular neuroscience : MN 46 20414742
1996 Embryonic expression of vasoactive intestinal peptide (VIP) and VIP receptor genes. Journal of neurochemistry 46 8627335
1988 The vasoactive intestinal peptide (VIP) receptor: recent data and hypothesis. Biochimie 46 2852963
2020 Developmental loss of MeCP2 from VIP interneurons impairs cortical function and behavior. eLife 45 32343226
2017 Neuroendocrine cells derived chemokine vasoactive intestinal polypeptide (VIP) in allergic diseases. Cytokine & growth factor reviews 45 28964637
2008 Structure-activity relationship of vasoactive intestinal peptide (VIP): potent agonists and potential clinical applications. Naunyn-Schmiedeberg's archives of pharmacology 45 18172612
2008 Enhancement of pulmonary vascular remodelling and inflammatory genes with VIP gene deletion. The European respiratory journal 43 18166594
1993 PACAP and VIP stimulate enzyme secretion in rat pancreatic acini via interaction with VIP/PACAP-2 receptors: additive augmentation of CCK/carbachol-induced enzyme release. Pancreas 42 8103217
1987 VIP- and CCK-like-immunoreactive neurons in the hedgehog (Erinaceus europaeus) and sheep (Ovis aries) brain. The Journal of comparative neurology 42 3312309
1985 Glucagon and VIP in the retina. Investigative ophthalmology & visual science 42 4044167
2000 VIP and the potent analog, stearyl-Nle(17)-VIP, induce proliferation of keratinocytes. FEBS letters 40 10858492
2003 The neuropeptides VIP/PACAP and T cells: inhibitors or activators? Current pharmaceutical design 39 12678866
2008 Urinary bladder function and somatic sensitivity in vasoactive intestinal polypeptide (VIP)-/- mice. Journal of molecular neuroscience : MN 38 18561033
1990 Characterization of VIP- and helodermin-preferring receptors on human small cell lung carcinoma cell lines. Peptides 38 1965034
2018 mTOR signaling in VIP neurons regulates circadian clock synchrony and olfaction. Proceedings of the National Academy of Sciences of the United States of America 37 29555746
2023 From CGRP to PACAP, VIP, and Beyond: Unraveling the Next Chapters in Migraine Treatment. Cells 36 37998384
2013 Antiproliferative effects of PACAP and VIP in serum-starved glioma cells. Journal of molecular neuroscience : MN 36 23900722
2012 Therapeutic potential of VIP vs PACAP in diabetes. Journal of molecular endocrinology 36 22991228
2005 Vasoactive intestinal peptide (VIP) induces c-fos expression in LNCaP prostate cancer cells through a mechanism that involves Ca2+ signalling. Implications in angiogenesis and neuroendocrine differentiation. Biochimica et biophysica acta 36 15921770
1990 Vasoactive intestinal peptide (VIP): an amnestic neuropeptide. Peptides 36 2178250
2006 VIP is a transcriptional target of Nurr1 in dopaminergic cells. Experimental neurology 35 16999955
2019 Nicotine excites VIP interneurons to disinhibit pyramidal neurons in auditory cortex. Synapse (New York, N.Y.) 34 31081950
2020 VIP Modulation of Hippocampal Synaptic Plasticity: A Role for VIP Receptors as Therapeutic Targets in Cognitive Decline and Mesial Temporal Lobe Epilepsy. Frontiers in cellular neuroscience 33 32595454
2016 Distinct Roles of SOM and VIP Interneurons during Cortical Up States. Frontiers in neural circuits 33 27507936
2010 VIP and PACAP. Results and problems in cell differentiation 33 19859678
1997 (Stearyl, Norleucine17)VIP hybrid antagonizes VIP receptors on non-small cell lung cancer cells. Life sciences 33 9363981
2011 VPAC1 (vasoactive intestinal peptide (VIP) receptor type 1) G protein-coupled receptor mediation of VIP enhancement of murine experimental colitis. Cellular immunology 32 21295288
2011 VIP-induced neuroprotection of the developing brain. Current pharmaceutical design 32 21524251
2003 VIP and drug design. Current pharmaceutical design 32 12570811
2021 The Vulvar Immunohistochemical Panel (VIP) Project: Molecular Profiles of Vulvar Squamous Cell Carcinoma. Cancers 31 34944993
2007 Vasoactive intestinal peptide (VIP) increases vascular endothelial growth factor (VEGF) expression and secretion in human breast cancer cells. Regulatory peptides 30 17683807
2003 VIP- and PACAP-mediated immunomodulation as prospective therapeutic tools. Trends in molecular medicine 30 12763526
1995 Role of VIP in the regulation of LH secretion in the female rat. Neuroscience and biobehavioral reviews 29 7630581
1990 Cardiac responses to VIP and VIP-ergic-cholinergic interaction in isolated dog heart preparations. European journal of pharmacology 29 2272357
2017 Multiple cell types form the VIP amacrine cell population. The Journal of comparative neurology 28 28472856
2016 VIP impairs acquisition of the macrophage proinflammatory polarization profile. Journal of leukocyte biology 28 27381006
2011 Immunomodulatory roles of VIP and PACAP in models of multiple sclerosis. Current pharmaceutical design 27 21524252
2011 VIP and growth factors in the infected cornea. Investigative ophthalmology & visual science 27 21666233
2006 VIP and PACAP regulate localized Ca2+ transients via cAMP-dependent mechanism. American journal of physiology. Cell physiology 27 16571863
1998 Analogues of VIP, helodermin, and PACAP discriminate between rat and human VIP1 and VIP2 receptors. Annals of the New York Academy of Sciences 27 9928018
2020 Different Roles for VIP Neurons in the Neonatal and Adult Suprachiasmatic Nucleus. Journal of biological rhythms 26 32536240
2018 Visible Immunoprecipitation (VIP) Assay: a Simple and Versatile Method forVisual Detection of Protein-protein Interactions. Bio-protocol 26 34179269
2012 Vasoactive intestinal peptide (VIP) inhibits human renal cell carcinoma proliferation. Biochimica et biophysica acta 26 22728770
2000 Vasoactive intestinal peptide (VIP) inhibits TGF-beta1 production in murine macrophages. Journal of neuroimmunology 26 10808055
1985 Evidence for common precursors but differential processing of VIP and PHM in VIP-producing tumors. Peptides 26 3840886
2012 Agnathan VIP, PACAP and their receptors: ancestral origins of today's highly diversified forms. PloS one 25 22957100
1986 Structure and expression of the vasoactive intestinal peptide (VIP) gene in a human tumor. Peptides 25 3748844
1995 A VIP hybrid antagonist: from developmental neurobiology to clinical applications. Cellular and molecular neurobiology 24 8719036
2020 Reduced VIP Expression Affects Circadian Clock Function in VIP-IRES-CRE Mice (JAX 010908). Journal of biological rhythms 23 32460660

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