VPAC<sub>2</sub> receptor | VIP and PACAP receptors | IUPHAR/BPS Guide to PHARMACOLOGY

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VPAC2 receptor

target has curated data in GtoImmuPdb

Target id: 372

Nomenclature: VPAC2 receptor

Family: VIP and PACAP receptors

Contents:

Gene and Protein Information
class B G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 438 7q36.3 VIPR2 vasoactive intestinal peptide receptor 2 26,40
Mouse 7 437 12 F2 Vipr2 vasoactive intestinal peptide receptor 2 23,26
Rat 7 437 6q33 Vipr2 vasoactive intestinal peptide receptor 2
Previous and Unofficial Names
PVR3 | VIP and PACAP receptor 2 | PACAP-R3 | pituitary adenylate cyclase-activating polypeptide type III receptor
Database Links
Specialist databases
GPCRDB vipr2_human (Hs), vipr2_mouse (Mm), vipr2_rat (Rn)
Other databases
CATH/Gene3D 4.10.1240.10
ChEMBL Target CHEMBL4532 (Hs)
Ensembl Gene ENSG00000106018 (Hs), ENSMUSG00000011171 (Mm), ENSRNOG00000004317 (Rn)
Entrez Gene 7434 (Hs), 22355 (Mm), 29555 (Rn)
Human Protein Atlas ENSG00000106018 (Hs)
KEGG Gene hsa:7434 (Hs), mmu:22355 (Mm), rno:29555 (Rn)
OMIM 601970 (Hs)
Orphanet ORPHA267074 (Hs)
Pharos P41587 (Hs)
RefSeq Nucleotide NM_003382 (Hs), NM_009511 (Mm), NM_017238 (Rn)
RefSeq Protein NP_003373 (Hs), NP_033537 (Mm), NP_058934 (Rn)
UniProtKB P41587 (Hs), P41588 (Mm), P35000 (Rn)
Wikipedia VIPR2 (Hs)
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Extracellular domain of VPAC2 receptor
PDB Id:  2X57
Resolution:  2.1Å
Species:  Human
References: 
Natural/Endogenous Ligands
GHRH {Sp: Human} , GHRH {Sp: Mouse} , GHRH {Sp: Rat}
PACAP-38 {Sp: Human, Mouse, Rat}
PACAP-27 {Sp: Human, Mouse, Rat, Sheep}
PHI {Sp: Mouse, Rat}
PHV {Sp: Rat}
secretin {Sp: Human} , secretin {Sp: Mouse} , secretin {Sp: Rat}
VIP {Sp: Human, Mouse, Rat}
Comments: VIP, PACAP-38 and PACAP-27 are the principal endogenous agonists
Potency order of endogenous ligands (Human)
VIP (VIP, P01282), PACAP-38 (ADCYAP1, P18509), PACAP-27 (ADCYAP1, P18509) > PHI >> GHRH (GHRH, P01286), secretin (SCT, P09683)

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Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[125I]VIP (human, mouse, rat) Hs Agonist 9.2 pKd 33
⤷ pKd 9.2 (Kd 7x10-10 M) [33]
Description: binding to membranes from CHO cells stably expressing the recombinant receptor
[125I]BAY 55-9837 Hs Agonist 9.2 pKd 41
⤷ pKd 9.2 (Kd 6.5x10-10 M) [41]
Description: binding to membranes from CHO cells stably expressing the recombinant receptor
VIP {Sp: Human, Mouse, Rat} Hs Agonist 7.8 – 8.8 pKi 32-33,47
⤷ pKi 8.8 (Ki 1.7x10-9 M) [33]
Description: inhibition of [125I]-VIP binding to membranes from CHO cells stably expressing the recombinant receptor
pKi 8.7 (Ki 1.8x10-9 M) [32]
Description: inhibition of [125I]-VIP binding to membranes from COS cells transiently expressing the recombinant receptor
pKi 7.8 (Ki 1.6x10-8 M) [47]
Description: inhibition of [125I]-VIP binding to CHO cells stably expressing the recombinant receptor
Ro 25-1392 Hs Agonist 8.0 pKi 47
⤷ pKi 8.0 (Ki 9.6x10-9 M) [47]
Description: inhibition of [125I]-VIP binding to CHO cells stably expressing the recombinant receptor
[Ala11,22,28]VIP Hs Agonist 5.6 pKi 33
⤷ pKi 5.6 (Ki 2.352x10-6 M) [33]
Description: inhibition of [125I]-VIP binding to membranes from CHO cells stably expressing the recombinant receptor
BAY 55-9837 Hs Agonist 9.4 pEC50 41
⤷ pEC50 9.4 (EC50 4x10-10 M) [41]
Description: cyclic AMP formation in CHO cells stably expressing recombinant receptor
PACAP-27 {Sp: Human, Mouse, Rat, Sheep} Hs Agonist 7.6 – 9.4 pEC50 9,30
⤷ pEC50 9.4 (EC50 3.8x10-10 M) [9]
Description: cyclic AMP formation in CHO cells stably expressing recombinant receptor
pEC50 8.4 (EC50 4x10-9 M) [30]
Description: stimulation of cyclic AMP formation in CHO cells stably expressing the recombinant receptor
pEC50 7.6 (EC50 2.39x10-8 M) [9]
Description: calcium influx in CHO cells stably expressing recombinant receptor
PACAP-38 {Sp: Human, Mouse, Rat} Hs Agonist 7.7 – 9.3 pEC50 9
⤷ pEC50 9.3 (EC50 5.3x10-10 M) [9]
Description: cyclic AMP formation in CHO cells stably expressing recombinant receptor
pEC50 7.7 (EC50 1.94x10-8 M) [9]
Description: calcium influx in CHO cells stably expressing recombinant receptor
Ro 25-1553 Hs Agonist 8.3 – 8.7 pEC50 24,30
⤷ pEC50 8.7 (EC50 2x10-9 M) [30]
Description: stimulation of cyclic AMP formation in CHO cells stably expressing the recombinant receptor
pEC50 8.3 (EC50 5x10-9 M) [24]
Description: cyclic AMP formation in CHO cells stably expressing recombinant receptor
Ro 25-1392 Hs Agonist 8.5 pEC50 47
⤷ pEC50 8.5 (EC50 3x10-9 M) [47]
Description: stimulation of cyclic AMP formation in CHO cells stably expressing the recombinant receptor
PG 99-465 Hs Partial agonist 8.3 – 8.4 pEC50 9
⤷ pEC50 8.4 (EC50 4.4x10-9 M) [9]
Description: inhibition of calcium influx stimulated by 30nM VIP in CHO cells stably expressing recombinant receptor
pEC50 8.3 (EC50 4.9x10-9 M) [9]
Description: cyclic AMP formation in CHO cells stably expressing recombinant receptor
VIP {Sp: Human, Mouse, Rat} Hs Agonist 7.3 – 9.3 pEC50 9,24,30,33,47
⤷ pEC50 9.3 (EC50 5x10-10 M) [33]
Description: stimulation of cyclic AMP formation in CHO cells stably expressing the recombinant receptor
pEC50 9.2 (EC50 6.3x10-10 M) [9]
Description: cyclic AMP formation in CHO cells stably expressing recombinant receptor
pEC50 8.5 (EC50 3x10-9 M) [30]
Description: stimulation of cyclic AMP formation in CHO cells stably expressing the recombinant receptor
pEC50 7.9 (EC50 1.4x10-8 M) [47]
Description: stimulation of cyclic AMP formation in CHO cells stably expressing the recombinant receptor
pEC50 7.8 (EC50 1.5x10-8 M) [24]
Description: cyclic AMP formation in CHO cells stably expressing recombinant receptor
pEC50 7.3 (EC50 5.09x10-8 M) [9]
Description: calcium influx in CHO cells stably expressing recombinant receptor
[Lys15,Arg16,Leu27]VIP-(1-7)/GRF-(8-27)-NH2 Hs Agonist <6.0 pEC50 30
⤷ pEC50 <6.0 (EC50 >1x10-6 M) [30]
Description: stimulation of cyclic AMP formation in CHO cells stably expressing the recombinant receptor
[Ala11,22,28]VIP Hs Agonist <5.0 – 5.9 pEC50 9,33
⤷ pEC50 5.9 (EC50 1.222x10-6 M) [33]
Description: stimulation of cyclic AMP formation in CHO cells stably expressing the recombinant receptor
pEC50 <5.0 (EC50 >1x10-5 M) [9]
Description: cyclic AMP formation in CHO cells stably expressing recombinant receptor
pEC50 <5.0 (EC50 >1x10-5 M) [9]
Description: calcium influx in CHO cells stably expressing recombinant receptor
N-stearyl-[Nle17]VIP Hs Agonist 9.0 pIC50 13
⤷ pIC50 9.0 (IC50 1x10-9 M) [13]
Description: inhibition of [125I]Ro25 1553 binding to membranes from CHO cells stably expressing the recombinant receptor
Ro 25-1553 Hs Agonist 7.8 – 9.5 pIC50 16,24,30
⤷ pIC50 7.8 – 9.5 (IC50 1.5x10-8 – 3x10-10 M) [16,24,30]
Description: inhibition of [125I]-VIP binding to membranes from CHO cells stably expressing the recombinant receptor
N-stearyl-[Nle17]VIP Rn Agonist 8.5 pIC50 13
⤷ pIC50 8.5 (IC50 3x10-9 M) [13]
Description: inhibition of [125I]Ro25 1553 binding to membranes from CHO cells stably expressing the recombinant receptor
helodermin Hs Agonist 8.5 pIC50 14
⤷ pIC50 8.5 (IC50 3x10-9 M) [14]
Description: inhibition of [125I]Ro25 1553 binding to membranes from CHO cells stably expressing the recombinant receptor
helodermin Rn Agonist 8.5 pIC50 14
⤷ pIC50 8.5 (IC50 3x10-9 M) [14]
Description: inhibition of [125I]Ro25 1553 binding to membranes from CHO cells stably expressing the recombinant receptor
VIP {Sp: Human, Mouse, Rat} Rn Agonist 8.0 – 8.4 pIC50 13-15
⤷ pIC50 8.4 (IC50 4x10-9 M) [15]
Description: Inhibition of [125I]VIP binding in membranes from CHO cells expressing recombinant receptor
pIC50 8.4 (IC50 4x10-9 M) [14]
Description: inhibition of [125I]Ro25 1553 binding to membranes from CHO cells stably expressing the recombinant receptor
pIC50 8.0 (IC50 1x10-8 M) [13]
Description: inhibition of [125I]Ro25 1553 binding to membranes from CHO cells stably expressing the recombinant receptor
PHV {Sp: Rat} Rn Agonist 8.2 pIC50 14
⤷ pIC50 8.2 (IC50 6x10-9 M) [14]
Description: inhibition of [125I]Ro25 1553 binding to membranes from CHO cells stably expressing the recombinant receptor
VIP {Sp: Human, Mouse, Rat} Hs Agonist 7.7 – 8.5 pIC50 13-15,24,30
⤷ pIC50 8.5 (IC50 3x10-9 M) [14]
Description: inhibition of [125I]Ro25 1553 binding to membranes from CHO cells stably expressing the recombinant receptor
pIC50 8.5 (IC50 3x10-9 M) [24]
Description: inhibition of [125I]Ro25 1553 binding to membranes from CHO cells stably expressing the recombinant receptor
pIC50 8.3 (IC50 5x10-9 M) [15]
Description: Inhibition of [125I]VIP binding in membranes from CHO cells expressing recombinant receptor
pIC50 8.0 (IC50 1x10-8 M) [13]
Description: inhibition of [125I]Ro25 1553 binding to membranes from CHO cells stably expressing the recombinant receptor
pIC50 7.7 (IC50 2x10-8 M) [30]
Description: inhibition of [125I]-VIP binding to membranes from CHO cells stably expressing the recombinant receptor
PACAP-27 {Sp: Human, Mouse, Rat, Sheep} Rn Agonist 8.0 pIC50 14
⤷ pIC50 8.0 (IC50 1x10-8 M) [14]
Description: inhibition of [125I]Ro25 1553 binding to membranes from CHO cells stably expressing the recombinant receptor
PHV {Sp: Rat} Hs Agonist 8.0 pIC50 14
⤷ pIC50 8.0 (IC50 1x10-8 M) [14]
Description: inhibition of [125I]Ro25 1553 binding to membranes from CHO cells stably expressing the recombinant receptor
PACAP-27 {Sp: Human, Mouse, Rat, Sheep} Hs Agonist 7.6 – 8.0 pIC50 14,30,41
⤷ pIC50 8.0 (IC50 1x10-8 M) [14]
Description: inhibition of [125I]Ro25 1553 binding to membranes from CHO cells stably expressing the recombinant receptor
pIC50 7.7 (IC50 2.1x10-8 M) [41]
Description: inhibition of [125I]-PACAP-27 binding to membranes from CHO cells stably expressing the recombinant receptor
pIC50 7.6 (IC50 2.5x10-8 M) [30]
Description: inhibition of [125I]-VIP binding to membranes from CHO cells stably expressing the recombinant receptor
PG 99-465 Hs Partial agonist 7.6 pIC50 9
⤷ pIC50 7.6 (IC50 2.29x10-8 M) [9]
Description: inhibition of cyclic AMP formation stimulated by 0.3nM VIP in CHO cells stably expressing recombinant receptor
PHI {Sp: Pig} Hs Agonist 7.5 pIC50 14
⤷ pIC50 7.5 (IC50 3x10-8 M) [14]
Description: inhibition of [125I]Ro25 1553 binding to membranes from CHO cells stably expressing the recombinant receptor
PHI {Sp: Pig} Rn Agonist 7.5 pIC50 14
⤷ pIC50 7.5 (IC50 3x10-8 M) [14]
Description: inhibition of [125I]Ro25 1553 binding to membranes from CHO cells stably expressing the recombinant receptor
BAY 55-9837 Hs Agonist 7.2 pIC50 41
⤷ pIC50 7.2 (IC50 6x10-8 M) [41]
Description: inhibition of [125I]-PACAP-27 binding to membranes from CHO cells stably expressing the recombinant receptor
secretin {Sp: Pig} Hs Agonist 5.3 pIC50 14-15
⤷ pIC50 5.3 (IC50 5x10-6 M) [15]
Description: Inhibition of [125I]VIP binding in membranes from CHO cells expressing recombinant receptor
pIC50 5.3 (IC50 5x10-6 M) [14]
Description: inhibition of [125I]Ro25 1553 binding to membranes from CHO cells stably expressing the recombinant receptor
[Arg16]chicken secretin Hs Agonist 5.3 pIC50 15
⤷ pIC50 5.3 (IC50 5x10-6 M) [15]
Description: Inhibition of [125I]VIP binding in membranes from CHO cells expressing recombinant receptor
[Lys15,Arg16,Leu27]VIP-(1-7)/GRF-(8-27)-NH2 Hs Agonist <4.5 – 6.0 pIC50 15,30
⤷ pIC50 <6.0 (IC50 >1x10-6 M) [30]
Description: inhibition of [125I]-VIP binding to membranes from CHO cells stably expressing the recombinant receptor
pIC50 <4.5 (IC50 >3x10-5 M) [15]
Description: Inhibition of [125I]VIP binding in membranes from CHO cells expressing recombinant receptor
[Arg16]chicken secretin Rn Agonist 5.0 pIC50 15
⤷ pIC50 5.0 (IC50 1x10-5 M) [15]
Description: Inhibition of [125I]VIP binding in membranes from CHO cells expressing recombinant receptor
secretin {Sp: Pig} Rn Agonist 4.5 pIC50 14-15
⤷ pIC50 4.5 (IC50 3x10-5 M) [14]
Description: inhibition of [125I]Ro25 1553 binding to membranes from CHO cells stably expressing the recombinant receptor
pIC50 4.5 (IC50 3x10-5 M) [15]
Description: Inhibition of [125I]VIP binding in membranes from CHO cells expressing recombinant receptor
[Lys15,Arg16,Leu27]VIP-(1-7)/GRF-(8-27)-NH2 Rn Agonist 4.5 pIC50 15
⤷ pIC50 4.5 (IC50 3x10-5 M) [15]
Description: Inhibition of [125I]VIP binding in membranes from CHO cells expressing recombinant receptor
[125I]PACAP-27 Hs Agonist - -
⤷
maxadilan Hs Full agonist - -
⤷
View species-specific agonist tables
Agonist Comments
Ro25-1553 is a selective VPAC2 agonist with much lower potency at VPAC1 and PAC1 receptors. Ro25-1392 and BAY 55-9837 display selectivity for VPAC2 over VPAC1 receptors.
Antagonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
PG 99-465 Hs Antagonist 8.7 pIC50 31
⤷ pIC50 8.7 (IC50 2x10-9 M) [31]
Description: inhibition of [125I]Ro25 1553 binding to membranes from CHO cells stably expressing the recombinant receptor
N-stearyl-[Nle17] neurotensin-(6-11)/VIP-(7-28) Hs Antagonist 7.3 pIC50 30
⤷ pIC50 7.3 (IC50 5x10-8 M) [30]
Description: inhibition of [125I]-VIP binding to membranes from CHO cells stably expressing the recombinant receptor
PG 97-269 Rn Antagonist 5.7 pIC50 12
⤷ pIC50 5.7 (IC50 2x10-6 M) [12]
Description: inhibition of [125I]-VIP binding to membranes from CHO cells stably expressing the recombinant receptor
PG 97-269 Hs Antagonist 5.5 – 5.7 pIC50 12,24
⤷ pIC50 5.7 (IC50 2x10-6 M) [24]
Description: inhibition of [125I]Ro25 1553 binding to membranes from CHO cells stably expressing the recombinant receptor
pIC50 5.5 (IC50 3x10-6 M) [12]
Description: inhibition of [125I]-VIP binding to membranes from CHO cells stably expressing the recombinant receptor
View species-specific antagonist tables
Antagonist Comments
PG99-465 has been used as a selective VPAC2 receptor antagonist in a number of physiological studies, but it may not be completely selective for this receptor subtype. A small molecule antagonist of human (but not mouse) VPAC2 receptors has been described, but has not yet been extensively characterised [4].
Immunopharmacology Comments
Monocytes from Sjögren's syndrome patients display increased VPAC2 receptor expression and impaired apoptotic cell phagocytosis [21]. The potential role of the VIP-PACAP system in immunity is reviewed in [11].
Primary Transduction Mechanisms
Transducer Effector/Response
Gs family Adenylate cyclase stimulation
References: 
Secondary Transduction Mechanisms
Transducer Effector/Response
G protein (identity unknown) Phospholipase C stimulation
Phospholipase D stimulation
References:  27-29
Tissue Distribution
Stroma of uterus and prostate; smooth muscles in gastrointestinal tract, seminal vesicles and skin; blood vessels; thymus;
Species:  Human
Technique:  Receptor autoradiography
References:  34-35
Pancreatic islets, lung, brain, stomach, colon
Species:  Mouse
Technique:  Northern blotting.
References:  23
Blood vessels in many tissues, e.g. renal cortex and skeletal muscle; alveoli of the lung; smooth muscle throughout the gastrointestinal tract; muscularis mucosa of the stomach; basal part of the mucosal epithelium of the colon; pancreatic acinar cells; follicular cells of the thyroid; adrenal medulla; smooth muscle of the fallopian tube, oviduct, uterus, epididymis and vas deferens; corpora cavernosa of the penis; retina
Species:  Mouse
Technique:  Receptor autoradiography
References:  20
Suprachiasmatic nuclei, thalamus, hypothalamus, midbrain, brainstem, hippocampus, olfactory bulb, dorsal horn of spinal cord, pituitary gland
Species:  Rat
Technique:  in situ hybridisation.
References:  38,42
Stomach (mucosal and external muscular layers), spleen, kidney, thymus, adrenal cortex, pancreatic islets, lung (bronchioles and vascular epithelium), epididymis, testis, ovary (granulosa cells), uterine smooth muscle
Species:  Rat
Technique:  in situ hybridisation.
References:  42
Stomach, lung, brainstem, diencephalon, small intestine, telencephalon
Species:  Rat
Technique:  Northern blotting.
References:  42
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Insulin release from MIN6 insulinoma cells.
Species:  Mouse
Tissue:  MIN6 insulinoma cells.
Response measured:  Insulin release.
References:  23
Stimulation of cAMP production in human SUP T1 lymphoma cells
Species:  Human
Tissue:  lymphoma cells
Response measured:  cAMP production
References:  16,40
Stimulation of cAMP production in mouse corticotroph tumour cells.
Species:  Mouse
Tissue:  Corticotroph tumour cells.
Response measured:  cAMP production.
References:  1
Physiological Functions
Studies in VPAC2 receptor null mice suggest that the receptor is essential for normal rhythmic activity of the circadian clock in the suprachiasmatic nuclei.
Species:  Mouse
Tissue:  Suprachiasmatic nuclei of the hypothalamus
References:  6,19,22
Studies in VPAC2 receptor null mice suggest that the receptor may play a role in growth, basal energy expenditure, and male reproductive functions.
Species:  Mouse
Tissue:  Whole animal
References:  2
A major neuroregulator of Th2/Th1 balance, mediating T cell chemotaxis, stimulation of some Th2-type cytokines and inhibition of some Th1-type cytokines, via decreased Th2 apoptosis, increased Th2-type cytokine production, and greater generation of Th2 memory cells.
Species:  Mouse
Tissue:  T lymphocytes
References:  10,44-46
Receptor upregulated in spinal dorsal horn following peripheral nerve injury, suggesting a role in the aetiology of neuropathic pain
Species:  Rat
Tissue:  Spinal Cord
References:  7-8
Mediates the relaxant effect of VIP in the rat gastric fundus
Species:  Rat
Tissue:  Gastric fundus
References:  36
Physiological Consequences of Altering Gene Expression
VPAC2 receptor-deficient mice showed retarded growth and had reduced serum IGF-I levels. Older male mutant mice exhibited diffuse seminiferous tubular degeneration with hypospermia and reduced fertility rate. The mutant mice appeared to have an increase in insulin sensitivity, increased lean mass and decreased fat mass with reduced serum leptin levels. Additionally, VPAC2 receptor-deficient mice had an increased basal metabolic rate.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  2
Transgenic mice overexpressing the human VPAC2 receptor from a yeast artificial chromosome construct resynchronized more quickly than wild-type controls to an advance of 8 h in the light-dark cycle and exhibited a significantly shorter circadian period in constant darkness, suggesting that the VPAC2 receptor can influence the rhythmicity and photic entrainment of the circadian clock.
Species:  Mouse
Tissue: 
Technique:  Transgenesis.
References:  37
Constitutive expression of the VPAC2 receptor selectively in CD4+ T cells (helper-inducer Th cells) in transgenic mice resulted in production of more Th2-type and less Th1-type cytokines after TCR activation, thus evoking an allergic state in normally nonallergic mice.
Species:  Mouse
Tissue: 
Technique:  Transgenesis.
References:  44-45
VPAC2 receptor null mice have normal basic immune characteristics, but display significantly enhanced delayed-type hypersensitivity and reduced immediate-type hypersensitivity, consistent with a role for the receptor in the maintenance of the normal ratio of Th2/Th1 cytokines.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  10,44,46
Reduced hippocampal neurogenesis, with a specific reduction in type 2 nestin-positive neural stem/precursor cells (NSPCs).
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  49
VPAC2 receptor null mice display enhanced induction of acute (but not chronic) colitis by dextran sodium sulfate
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  48
VPAC2 receptor null mice exhibit a loss of normal circadian rhythms of electrical activity and clock gene expression in the suprachiasmatic nucleus (SCN). Consequently, rhythms of physiology (heart rate, blood pressure, body temperature and metabolic rate) and behaviour (activity, sleep/wake and feeding) are lost when animals are placed under constant conditions. When kept in a light/dark cycle, ryhtms of physiology and behaviour are phase advanced compared to wild-type mice. VIP null mice display a similar circadian phenotype, suggesting that VIP functions as the endogenous ligand of the VPAC2 receptor in the control of circadian rhythms in the SCN.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  3,5-6,18-19,22,39
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Vipr2tm1Ajh Vipr2tm1Ajh/Vipr2tm1Ajh
B6.129P2-Vipr2		 MGI:107166  MP:0002559 abnormal circadian persistence PMID: 12086606  15071099 
Vipr2tm1Ajh Vipr2tm1Ajh/Vipr2tm1Ajh
B6.129P2-Vipr2		 MGI:107166  MP:0001502 abnormal circadian rhythm PMID: 12086606 
Vipr2tm1Ajh Vipr2tm1Ajh/Vipr2tm1Ajh
involves: 129P2/OlaHsd * C57BL/6J		 MGI:107166  MP:0001502 abnormal circadian rhythm PMID: 12086606 
Vipr2tm1Ejg Vipr2tm1Ejg/Vipr2tm1Ejg
B6.129P2-Vipr2		 MGI:107166  MP:0003009 abnormal cytokine secretion PMID: 11698667 
Vipr2tm1Ajh Vipr2tm1Ajh/Vipr2tm1Ajh
B6.129P2-Vipr2		 MGI:107166  MP:0002560 arrhythmic circadian persistence PMID: 12086606  15071099 
Vipr2tm1Ajh Vipr2tm1Ajh/Vipr2tm1Ajh
involves: 129P2/OlaHsd * C57BL/6J		 MGI:107166  MP:0002560 arrhythmic circadian persistence PMID: 12086606 
Vipr2tm1Hmh Vipr2tm1Hmh/Vipr2tm1Hmh
involves: 129P2/OlaHsd * C57BL/6		 MGI:107166  MP:0001258 decreased body length PMID: 12239111 
Vipr2tm1Hmh Vipr2tm1Hmh/Vipr2tm1Hmh
involves: 129P2/OlaHsd * C57BL/6		 MGI:107166  MP:0001262 decreased body weight PMID: 12239111 
Vipr2tm1Hmh Vipr2tm1Hmh/Vipr2tm1Hmh
involves: 129P2/OlaHsd * C57BL/6		 MGI:107166  MP:0004701 decreased circulating insulin-like growth factor I level PMID: 12239111 
Vipr2tm1Hmh Vipr2tm1Hmh/Vipr2tm1Hmh
involves: 129P2/OlaHsd * C57BL/6		 MGI:107166  MP:0003910 decreased eating behavior PMID: 12239111 
Vipr2tm1Ejg Vipr2tm1Ejg/Vipr2tm1Ejg
B6.129P2-Vipr2		 MGI:107166  MP:0002492 decreased IgE level PMID: 11698667 
Vipr2tm1Ejg Vipr2tm1Ejg/Vipr2tm1Ejg
B6.129P2-Vipr2		 MGI:107166  MP:0008700 decreased interleukin-4 secretion PMID: 11698667 
Vipr2tm1Ejg Vipr2tm1Ejg/Vipr2tm1Ejg
B6.129P2-Vipr2		 MGI:107166  MP:0005597 decreased susceptibility to type I hypersensitivity reaction PMID: 11698667 
Vipr2tm1Hmh Vipr2tm1Hmh/Vipr2tm1Hmh
involves: 129P2/OlaHsd * C57BL/6		 MGI:107166  MP:0010025 decreased total body fat amount PMID: 12239111 
Vipr2tm1Ajh Vipr2tm1Ajh/Vipr2tm1Ajh
B6.129P2-Vipr2		 MGI:107166  MP:0001402 hypoactivity PMID: 12086606 
Vipr2tm1Hmh Vipr2tm1Hmh/Vipr2tm1Hmh
involves: 129P2/OlaHsd * C57BL/6		 MGI:107166  MP:0005480 increased circulating triiodothyronine level PMID: 12239111 
Vipr2tm1Hmh Vipr2tm1Hmh/Vipr2tm1Hmh
involves: 129P2/OlaHsd * C57BL/6		 MGI:107166  MP:0002891 increased insulin sensitivity PMID: 12239111 
Vipr2tm1Ejg Vipr2tm1Ejg/Vipr2tm1Ejg
B6.129P2-Vipr2		 MGI:107166  MP:0008566 increased interferon-gamma secretion PMID: 11698667 
Vipr2tm1Ejg Vipr2tm1Ejg/Vipr2tm1Ejg
B6.129P2-Vipr2		 MGI:107166  MP:0008687 increased interleukin-2 secretion PMID: 11698667 
Vipr2tm1Hmh Vipr2tm1Hmh/Vipr2tm1Hmh
involves: 129P2/OlaHsd * C57BL/6		 MGI:107166  MP:0003960 increased lean body mass PMID: 12239111 
Vipr2tm1Ejg Vipr2tm1Ejg/Vipr2tm1Ejg
B6.129P2-Vipr2		 MGI:107166  MP:0005617 increased susceptibility to type IV hypersensitivity reaction PMID: 11698667 
Vipr2tm1Hmh Vipr2tm1Hmh/Vipr2tm1Hmh
involves: 129P2/OlaHsd * C57BL/6		 MGI:107166  MP:0001922 reduced male fertility PMID: 12239111 
Vipr2tm1Hmh Vipr2tm1Hmh/Vipr2tm1Hmh
involves: 129P2/OlaHsd * C57BL/6		 MGI:107166  MP:0001154 seminiferous tubule degeneration PMID: 12239111 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Schizophrenia 16; SCZD16
Synonyms: Schizophrenia [Orphanet: ORPHA3140] [OMIM: 181500] [Disease Ontology: DOID:5419]
Disease Ontology: DOID:5419
OMIM: 181500, 613959
Orphanet: ORPHA3140
Comments:  Two groups have shown that copy number variation leading to duplications of the VIPR2 gene confers significant risk for schizophrenia.
References:  25,43
Biologically Significant Variants
Type:  Splice variants.
Species:  Mouse
Description:  A deletion variant of mouse VPAC2 has been identified in immune cells that lacks amino acids 367-380 at the carboxyl-terminal end of the seventh transmembrane domain. The variant did not transduce VIP-elicited increases in intracellular concentration of cyclic AMP, chemotaxis, or suppression of generation of interleukin-2, without apparent alterations of expression or ligand binding.
References:  17

References

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1. Aoki Y, Iwasaki Y, Katahira M, Oiso Y, Saito H. (1997) Regulation of the rat proopiomelanocortin gene expression in AtT-20 cells. II: Effects of the pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal polypeptide. Endocrinology, 138 (5): 1930-4. [PMID:9112389]

2. Asnicar MA, Köster A, Heiman ML, Tinsley F, Smith DP, Galbreath E, Fox N, Ma YL, Blum WF, Hsiung HM. (2002) Vasoactive intestinal polypeptide/pituitary adenylate cyclase-activating peptide receptor 2 deficiency in mice results in growth retardation and increased basal metabolic rate. Endocrinology, 143 (10): 3994-4006. [PMID:12239111]

3. Bechtold DA, Brown TM, Luckman SM, Piggins HD. (2008) Metabolic rhythm abnormalities in mice lacking VIP-VPAC2 signaling. Am. J. Physiol. Regul. Integr. Comp. Physiol., 294 (2): R344-51. [PMID:18032467]

4. Chu A, Caldwell JS, Chen YA. (2010) Identification and characterization of a small molecule antagonist of human VPAC(2) receptor. Mol. Pharmacol., 77 (1): 95-101. [PMID:19854890]

5. Colwell CS, Michel S, Itri J, Rodriguez W, Tam J, Lelievre V, Hu Z, Liu X, Waschek JA. (2003) Disrupted circadian rhythms in VIP- and PHI-deficient mice. Am. J. Physiol. Regul. Integr. Comp. Physiol., 285 (5): R939-49. [PMID:12855416]

6. Cutler DJ, Haraura M, Reed HE, Shen S, Sheward WJ, Morrison CF, Marston HM, Harmar AJ, Piggins HD. (2003) The mouse VPAC2 receptor confers suprachiasmatic nuclei cellular rhythmicity and responsiveness to vasoactive intestinal polypeptide in vitro. Eur. J. Neurosci., 17 (2): 197-204. [PMID:12542655]

7. Dickinson T, Fleetwood-Walker SM. (1999) VIP and PACAP: very important in pain?. Trends Pharmacol. Sci., 20 (8): 324-9. [PMID:10431211]

8. Dickinson T, Mitchell R, Robberecht P, Fleetwood-Walker SM. (1999) The role of VIP/PACAP receptor subtypes in spinal somatosensory processing in rats with an experimental peripheral mononeuropathy. Neuropharmacology, 38 (1): 167-80. [PMID:10193908]

9. Dickson L, Aramori I, McCulloch J, Sharkey J, Finlayson K. (2006) A systematic comparison of intracellular cyclic AMP and calcium signalling highlights complexities in human VPAC/PAC receptor pharmacology. Neuropharmacology, 51 (6): 1086-98. [PMID:16930633]

10. Goetzl EJ, Voice JK, Shen S, Dorsam G, Kong Y, West KM, Morrison CF, Harmar AJ. (2001) Enhanced delayed-type hypersensitivity and diminished immediate-type hypersensitivity in mice lacking the inducible VPAC(2) receptor for vasoactive intestinal peptide. Proc. Natl. Acad. Sci. U.S.A., 98 (24): 13854-9. [PMID:11698667]

11. Gomariz RP, Juarranz Y, Abad C, Arranz A, Leceta J, Martinez C. (2006) VIP-PACAP system in immunity: new insights for multitarget therapy. Ann. N. Y. Acad. Sci., 1070: 51-74. [PMID:16888149]

12. Gourlet P, De Neef P, Cnudde J, Waelbroeck M, Robberecht P. (1997) In vitro properties of a high affinity selective antagonist of the VIP1 receptor. Peptides, 18 (10): 1555-60. [PMID:9437716]

13. Gourlet P, Rathé J, De Neef P, Cnudde J, Vandermeers-Piret MC, Waelbroeck M, Robberecht P. (1998) Interaction of lipophilic VIP derivatives with recombinant VIP1/PACAP and VIP2/PACAP receptors. Eur. J. Pharmacol., 354 (1): 105-11. [PMID:9726637]

14. Gourlet P, Vandermeers A, Van Rampelbergh J, De Neef P, Cnudde J, Waelbroeck M, Robberecht P. (1998) Analogues of VIP, helodermin, and PACAP discriminate between rat and human VIP1 and VIP2 receptors. Ann. N. Y. Acad. Sci., 865: 247-52. [PMID:9928018]

15. Gourlet P, Vandermeers A, Vertongen P, Rathe J, De Neef P, Cnudde J, Waelbroeck M, Robberecht P. (1997) Development of high affinity selective VIP1 receptor agonists. Peptides, 18 (10): 1539-45. [PMID:9437714]

16. Gourlet P, Vertongen P, Vandermeers A, Vandermeers-Piret MC, Rathe J, De Neef P, Waelbroeck M, Robberecht P. (1997) The long-acting vasoactive intestinal polypeptide agonist RO 25-1553 is highly selective of the VIP2 receptor subclass. Peptides, 18 (3): 403-8. [PMID:9145428]

17. Grinninger C, Wang W, Oskoui KB, Voice JK, Goetzl EJ. (2004) A natural variant type II G protein-coupled receptor for vasoactive intestinal peptide with altered function. J. Biol. Chem., 279: 40259-40262. [PMID:15302876]

18. Hannibal J, Hsiung HM, Fahrenkrug J. (2011) Temporal phasing of locomotor activity, heart rate rhythmicity, and core body temperature is disrupted in VIP receptor 2-deficient mice. Am. J. Physiol. Regul. Integr. Comp. Physiol., 300 (3): R519-30. [PMID:21178124]

19. Harmar AJ, Marston HM, Shen S, Spratt C, West KM, Sheward WJ, Morrison CF, Dorin JR, Piggins HD, Reubi JC et al.. (2002) The VPAC(2) receptor is essential for circadian function in the mouse suprachiasmatic nuclei. Cell, 109 (4): 497-508. [PMID:12086606]

20. Harmar AJ, Sheward WJ, Morrison CF, Waser B, Gugger M, Reubi JC. (2004) Distribution of the VPAC2 receptor in peripheral tissues of the mouse. Endocrinology, 145 (3): 1203-10. [PMID:14617572]

21. Hauk V, Fraccaroli L, Grasso E, Eimon A, Ramhorst R, Hubscher O, Pérez Leirós C. (2014) Monocytes from Sjögren's syndrome patients display increased vasoactive intestinal peptide receptor 2 expression and impaired apoptotic cell phagocytosis. Clin. Exp. Immunol., 177 (3): 662-70. [PMID:24827637]

22. Hughes AT, Fahey B, Cutler DJ, Coogan AN, Piggins HD. (2004) Aberrant gating of photic input to the suprachiasmatic circadian pacemaker of mice lacking the VPAC2 receptor. J. Neurosci., 24 (14): 3522-6. [PMID:15071099]

23. Inagaki N, Yoshida H, Mizuta M, Mizuno N, Fujii Y, Gonoi T, Miyazaki J, Seino S. (1994) Cloning and functional characterization of a third pituitary adenylate cyclase-activating polypeptide receptor subtype expressed in insulin-secreting cells. Proc. Natl. Acad. Sci. U.S.A., 91 (7): 2679-83. [PMID:8146174]

24. Juarranz MG, Van Rampelbergh J, Gourlet P, De Neef P, Cnudde J, Robberecht P, Waelbroeck M. (1999) Different vasoactive intestinal polypeptide receptor domains are involved in the selective recognition of two VPAC(2)-selective ligands. Mol. Pharmacol., 56 (6): 1280-7. [PMID:10570056]

25. Levinson DF, Duan J, Oh S, Wang K, Sanders AR, Shi J, Zhang N, Mowry BJ, Olincy A, Amin F et al.. (2011) Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. Am J Psychiatry, 168 (3): 302-16. [PMID:21285140]

26. Mackay M, Fantes J, Scherer S, Boyle S, West K, Tsui LC, Belloni E, Lutz E, Van Heyningen V, Harmar AJ. (1996) Chromosomal localization in mouse and human of the vasoactive intestinal peptide receptor type 2 gene: a possible contributor to the holoprosencephaly 3 phenotype. Genomics, 37 (3): 345-53. [PMID:8938447]

27. MacKenzie CJ, Lutz EM, Johnson MS, Robertson DN, Holland PJ, Mitchell R. (2001) Mechanisms of phospholipase C activation by the vasoactive intestinal polypeptide/pituitary adenylate cyclase-activating polypeptide type 2 receptor. Endocrinology, 142 (3): 1209-17. [PMID:11181537]

28. MacKenzie CJ, Lutz EM, McCulloch DA, Mitchell R, Harmar AJ. (1996) Phospholipase C activation by VIP1 and VIP2 receptors expressed in COS 7 cells involves a pertussis toxin-sensitive mechanism. Ann. N. Y. Acad. Sci., 805: 579-84. [PMID:8993443]

29. McCulloch DA, Lutz EM, Johnson MS, Robertson DN, MacKenzie CJ, Holland PJ, Mitchell R. (2001) ADP-ribosylation factor-dependent phospholipase D activation by VPAC receptors and a PAC(1) receptor splice variant. Mol. Pharmacol., 59 (6): 1523-32. [PMID:11353814]

30. Moody TW, Jensen RT, Fridkin M, Gozes I. (2002) (N-stearyl, norleucine17)VIPhybrid is a broad spectrum vasoactive intestinal peptide receptor antagonist. J. Mol. Neurosci., 18 (1-2): 29-35. [PMID:11931347]

31. Moreno D, Gourlet P, De Neef P, Cnudde J, Waelbroeck M, Robberecht P. (2000) Development of selective agonists and antagonists for the human vasoactive intestinal polypeptide VPAC(2) receptor. Peptides, 21 (10): 1543-9. [PMID:11068102]

32. Nicole P, Du K, Couvineau A, Laburthe M. (1998) Site-directed mutagenesis of human vasoactive intestinal peptide receptor subtypes VIP1 and VIP2: evidence for difference in the structure-function relationship. J. Pharmacol. Exp. Ther., 284 (2): 744-50. [PMID:9454823]

33. Nicole P, Lins L, Rouyer-Fessard C, Drouot C, Fulcrand P, Thomas A, Couvineau A, Martinez J, Brasseur R, Laburthe M. (2000) Identification of key residues for interaction of vasoactive intestinal peptide with human VPAC1 and VPAC2 receptors and development of a highly selective VPAC1 receptor agonist. Alanine scanning and molecular modeling of the peptide. J. Biol. Chem., 275 (31): 24003-12. [PMID:10801840]

34. Reubi JC. (2000) In vitro evaluation of VIP/PACAP receptors in healthy and diseased human tissues. Clinical implications. Ann. N. Y. Acad. Sci., 921: 1-25. [PMID:11193811]

35. Reubi JC, Läderach U, Waser B, Gebbers JO, Robberecht P, Laissue JA. (2000) Vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor subtypes in human tumors and their tissues of origin. Cancer Res., 60 (11): 3105-12. [PMID:10850463]

36. Robberecht P, De Neef P, Lefebvre RA. (1998) Influence of selective VIP receptor agonists in the rat gastric fundus. Eur. J. Pharmacol., 359 (1): 77-80. [PMID:9831296]

37. Shen S, Spratt C, Sheward WJ, Kallo I, West K, Morrison CF, Coen CW, Marston HM, Harmar AJ. (2000) Overexpression of the human VPAC2 receptor in the suprachiasmatic nucleus alters the circadian phenotype of mice. Proc. Natl. Acad. Sci. U.S.A., 97 (21): 11575-80. [PMID:11027354]

38. Sheward WJ, Lutz EM, Harmar AJ. (1995) The distribution of vasoactive intestinal peptide2 receptor messenger RNA in the rat brain and pituitary gland as assessed by in situ hybridization. Neuroscience, 67 (2): 409-18. [PMID:7675176]

39. Sheward WJ, Naylor E, Knowles-Barley S, Armstrong JD, Brooker GA, Seckl JR, Turek FW, Holmes MC, Zee PC, Harmar AJ. (2010) Circadian control of mouse heart rate and blood pressure by the suprachiasmatic nuclei: behavioral effects are more significant than direct outputs. PLoS ONE, 5 (3): e9783. [PMID:20339544]

40. Svoboda M, Tastenoy M, Van Rampelbergh J, Goossens JF, De Neef P, Waelbroeck M, Robberecht P. (1994) Molecular cloning and functional characterization of a human VIP receptor from SUP-T1 lymphoblasts. Biochem. Biophys. Res. Commun., 205 (3): 1617-24. [PMID:7811244]

41. Tsutsumi M, Claus TH, Liang Y, Li Y, Yang L, Zhu J, Dela Cruz F, Peng X, Chen H, Yung SL et al.. (2002) A potent and highly selective VPAC2 agonist enhances glucose-induced insulin release and glucose disposal: a potential therapy for type 2 diabetes. Diabetes, 51 (5): 1453-60. [PMID:11978642]

42. Usdin TB, Bonner TI, Mezey E. (1994) Two receptors for vasoactive intestinal polypeptide with similar specificity and complementary distributions. Endocrinology, 135 (6): 2662-80. [PMID:7988457]

43. Vacic V, McCarthy S, Malhotra D, Murray F, Chou HH, Peoples A, Makarov V, Yoon S, Bhandari A, Corominas R et al.. (2011) Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia. Nature, 471 (7339): 499-503. [PMID:21346763]

44. Voice JK, Dorsam G, Chan RC, Grinninger C, Kong Y, Goetzl EJ. (2002) Immunoeffector and immunoregulatory activities of vasoactive intestinal peptide. Regul. Pept., 109 (1-3): 199-208. [PMID:12409234]

45. Voice JK, Dorsam G, Lee H, Kong Y, Goetzl EJ. (2001) Allergic diathesis in transgenic mice with constitutive T cell expression of inducible vasoactive intestinal peptide receptor. FASEB J., 15 (13): 2489-96. [PMID:11689474]

46. Voice JK, Grinninger C, Kong Y, Bangale Y, Paul S, Goetzl EJ. (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. J. Immunol., 170 (1): 308-14. [PMID:12496414]

47. Xia M, Sreedharan SP, Bolin DR, Gaufo GO, Goetzl EJ. (1997) Novel cyclic peptide agonist of high potency and selectivity for the type II vasoactive intestinal peptide receptor. J. Pharmacol. Exp. Ther., 281 (2): 629-33. [PMID:9152366]

48. Yadav M, Huang MC, Goetzl EJ. (2011) VPAC1 (vasoactive intestinal peptide (VIP) receptor type 1) G protein-coupled receptor mediation of VIP enhancement of murine experimental colitis. Cell. Immunol., 267 (2): 124-32. [PMID:21295288]

49. Zaben M, Sheward WJ, Shtaya A, Abbosh C, Harmar AJ, Pringle AK, Gray WP. (2009) The neurotransmitter VIP expands the pool of symmetrically dividing postnatal dentate gyrus precursors via VPAC2 receptors or directs them toward a neuronal fate via VPAC1 receptors. Stem Cells, 27 (10): 2539-51. [PMID:19650041]

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