{"gene":"VIPR2","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2002,"finding":"VPAC2 receptor (encoded by Vipr2) is essential for circadian function in the mouse SCN: Vipr2-/- mice cannot sustain circadian rhythms of rest/activity behavior, fail to show circadian expression of core clock genes mPer1, mPer2, and mCry1 and the clock-controlled gene AVP in the SCN, and fail to show acute induction of mPer1 and mPer2 by nocturnal illumination.","method":"Vipr2 null mouse knockout; behavioral monitoring; clock gene expression analysis by in situ hybridization/Northern blot","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple defined molecular and behavioral phenotypes, highly cited and foundational study","pmids":["12086606"],"is_preprint":false},{"year":2003,"finding":"VPAC2 receptor is necessary for the major part of the electrophysiological actions of VIP on SCN neurons in vitro: fewer SCN cells from Vipr2-/- mice responded to VIP and the VPAC2-selective agonist Ro 25-1553; VIP-evoked responses in control SCN neurons were attenuated by the selective VPAC2 antagonist PG 99-465. Additionally, the midday peak in SCN electrical firing rate rhythm was lost in Vipr2-/- mice and mimicked in controls by chronic VPAC2 antagonist treatment.","method":"Electrophysiological recording of SCN neurons in brain slices from Vipr2-/- and wild-type mice; pharmacological blockade with selective VPAC2 agonist and antagonist","journal":"The European journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mice plus pharmacological confirmation with selective agonist/antagonist, multiple orthogonal electrophysiological readouts","pmids":["12542655"],"is_preprint":false},{"year":2004,"finding":"In Vipr2-/- mice, photic gating of input to the SCN is abolished: spontaneous circadian variation in pERK and c-FOS is absent, and light pulses given during both subjective day and subjective night robustly increase pERK and c-FOS (versus only subjective night in wild-type), indicating that VPAC2 signaling is required for temporal gating of photic input to the SCN circadian pacemaker.","method":"Immunohistochemical detection of pERK and c-FOS in Vipr2-/- and wild-type SCN under LD and DD conditions with light pulse experiments","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO model with two orthogonal molecular readouts (pERK, c-FOS), rigorously controlled under multiple lighting conditions","pmids":["15071099"],"is_preprint":false},{"year":2000,"finding":"Overexpression of the human VPAC2 receptor in the SCN shortens the circadian period in constant darkness and accelerates resynchronization after an 8-h advance of the LD cycle, demonstrating that the level of VPAC2R expression directly influences the period and photic entrainment of the circadian clock.","method":"Transgenic mice overexpressing human VPAC2R from a YAC construct; wheel-running behavior monitoring in LD and constant darkness","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — transgenic gain-of-function model with quantitative behavioral phenotypes, complementary to null mutant data","pmids":["11027354"],"is_preprint":false},{"year":2001,"finding":"Loss of VPAC2R in mice shifts T cell cytokine balance: VPAC2R-null mice show enhanced delayed-type hypersensitivity with increased IL-2 and IFN-γ (Th1 cytokines) and reduced IL-4 (Th2 cytokine) from splenic CD4+ T cells, and markedly lower IgE anti-hapten and cutaneous anaphylaxis, demonstrating that VIP-VPAC2R signaling normally maintains Th2/Th1 cytokine ratio.","method":"Vipr2-/- null mouse; hapten-evoked DTH assay; splenic CD4+ T cell cytokine production; serum Ig measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple immune readouts (DTH, anaphylaxis, cytokines, Ig), clearly mechanistic","pmids":["11698667"],"is_preprint":false},{"year":2004,"finding":"VIP binding to VPAC2 on CD4 T cells specifically induces up-regulation of the Th2-type transcription factors c-Maf and JunB (but not GATA3, T-bet, or NFATc), which leads to enhanced IL-4 and IL-5 production, establishing the molecular mechanism by which VPAC2 promotes Th2 differentiation.","method":"Analysis of transcription factor mRNA, protein and activity in TCR-stimulated CD4 T cells from VPAC2 transgenic, knockout, and wild-type mice; IL-4 and IL-5 measurement","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — transgenic vs. KO comparison, multiple orthogonal readouts (mRNA, protein, activity), specific transcription factor identification","pmids":["15187104"],"is_preprint":false},{"year":2005,"finding":"VIP-VPAC2 signaling is required for SCN cellular rhythmicity: in Vipr2-/- mice, only a small minority of SCN cells exhibit circadian firing patterns; exogenous GRP can promote SCN cellular rhythms in Vipr2-/- slices via BB2 receptors, while BB2 receptor blockade in wild-type mice suppresses neuronal oscillations only when VPAC2 receptors are also blocked.","method":"Electrophysiological recording of individual SCN neurons in brain slices from Vipr2-/- and wild-type mice; pharmacological application of GRP and BB2/VPAC2 receptor antagonists","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO model plus pharmacological rescue with orthogonal neuropeptide, establishing pathway redundancy","pmids":["16319315"],"is_preprint":false},{"year":2007,"finding":"VPAC2R-null mice lacking a functional SCN clock retain strongly rhythmic hepatic clock gene expression (advanced in phase), entrained by food intake timing rather than light; both genotypes develop food-anticipatory activity rhythms under restricted feeding, demonstrating that VPAC2-dependent SCN function is not required for food-entrainable peripheral oscillator function.","method":"Vipr2-/- mice; wheel-running, corticosterone secretion, hepatic clock gene expression under normal and restricted feeding regimens","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO model with multiple physiological outputs and restricted feeding paradigm, clear epistatic placement of VPAC2 in light vs. food entrainment pathways","pmids":["17442819"],"is_preprint":false},{"year":2007,"finding":"In Vipr2-/- mice and VIP-deficient mice, daily metabolic and feeding rhythms are advanced (peak in late day rather than early night) under LD conditions, and are abolished under constant light, demonstrating that VIP-VPAC2 signaling controls temporal organization of metabolism and feeding behavior.","method":"Metabolic monitoring (indirect calorimetry), feeding behavior, and wheel-running in Vipr2-/- and VIP-deficient mice under LD and constant light","journal":"American journal of physiology. Regulatory, integrative and comparative physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — parallel KO models with quantitative metabolic phenotypes confirm VPAC2 requirement for metabolic rhythm","pmids":["18032467"],"is_preprint":false},{"year":2007,"finding":"In gastric smooth muscle, VPAC2 receptor desensitization is mediated exclusively by GRK2: VIP induces GRK2-mediated phosphorylation of VPAC2, followed by internalization and desensitization; PKA-mediated phosphorylation of GRK2 at Ser685 augments its kinase activity and Gβγ binding, enhancing VPAC2 receptor phosphorylation, internalization, and desensitization.","method":"Expression of kinase-deficient GRK2(K220R) and PKA-site deficient GRK2(S685A) mutants; PKA inhibitor (PKI); 125I-VIP binding; receptor biotinylation; adenylyl cyclase activity and cAMP assays in smooth muscle cells","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis of kinase and phosphorylation sites combined with functional desensitization assays, multiple orthogonal methods in smooth muscle system","pmids":["18077607"],"is_preprint":false},{"year":2006,"finding":"Cross-regulation of VPAC2 receptor desensitization by M3 muscarinic receptors: ACh activation of M3 receptors inhibits GRK2-mediated VPAC2 receptor phosphorylation, internalization and desensitization via PKC-mediated phosphorylation of RKIP at Ser153, which causes RKIP to dissociate from Raf-1 and instead bind and inhibit GRK2. In muscle cells expressing RKIP(S153A), this cross-regulatory mechanism is abolished.","method":"PKC inhibitors; RKIP(S153A) mutant expression in smooth muscle cells; RKIP-GRK2 and RKIP-Raf association by co-IP; VPAC2 phosphorylation, internalization, ERK1/2 activity assays","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — phosphorylation-site mutagenesis, co-IP, and multiple functional assays establish the cross-talk mechanism","pmids":["17170028"],"is_preprint":false},{"year":2008,"finding":"In individual SCN neurons from Vipr2-/- mice, fewer cells express detectable Per1-driven GFP rhythms, the oscillation amplitude is significantly lower, and cells are poorly synchronized with each other compared with wild-type; pharmacological VPAC2 receptor blockade in wild-type SCN partially mimics the Vipr2-/- phenotype, demonstrating that VPAC2 intercellular signaling is required for robust, synchronous clock gene oscillations at the single-cell level.","method":"Real-time confocal live imaging of destabilized GFP driven by Per1 in SCN-containing brain slices from Vipr2-/- and wild-type mice; VPAC2 pharmacological blockade","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — live imaging with genetic KO and pharmacological confirmation, single-cell resolution","pmids":["18554318"],"is_preprint":false},{"year":2013,"finding":"VPAC2 receptor interacts physically with all three RAMPs (RAMP1, RAMP2, RAMP3), enhancing their cell surface expression; this VPAC2-RAMP interaction modulates G-protein coupling in an agonist-specific manner, though cAMP production is not affected.","method":"Co-transfection of VPAC2 with RAMPs in HEK293S and CHO-K1 cells; ELISA for cell-surface RAMP/receptor expression; GTPγS binding to Gs, Gi, G12, Gq; cAMP assays","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell surface ELISA and G-protein coupling assays in co-transfected cells, single lab but multiple readouts","pmids":["22946657"],"is_preprint":false},{"year":2013,"finding":"VPAC2 localizes to primary cilia in neurons and glial cells of multiple brain regions including the SCN and thalamus; the C-terminus of VPAC2 is both necessary and sufficient for ciliary targeting, with a tetrapeptide RDYR motif serving as the ciliary targeting signal; ciliary targeting requires Tubby, the BBSome, and the BBSome-targeting factor Arl6.","method":"Endogenous VPAC2 immunofluorescence in brain sections; C-terminus deletion/truncation constructs; RDYR motif mutagenesis; knockdown of Tubby, BBSome subunits, and Arl6","journal":"Biology open","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis of targeting signal combined with genetic knockdown of targeting machinery and localization imaging","pmids":["23862016"],"is_preprint":false},{"year":2005,"finding":"VPAC2 receptors mediate the PKC-dependent neuroprotective effects of VIP against neonatal excitotoxic brain lesions: VIP effects were mimicked by VPAC2 agonists and PHI but not VPAC1 agonists or PACAP; neuroprotection was lost in Vipr2-/- mice; protection is independent of cAMP and mediated by protein kinase C.","method":"Vipr2-/- mice and pharmacological agonist/antagonist approach in the ibotenate neonatal excitotoxicity mouse model; in situ hybridization for VPAC2 mRNA; VIP-specific binding assays","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO combined with receptor subtype-selective pharmacology and mechanistic pathway dissection (cAMP-independent, PKC-dependent)","pmids":["15872042"],"is_preprint":false},{"year":2004,"finding":"VPAC2 receptor activation mediates lipolysis in primary rat adipocytes: VPAC2-selective agonists (Hexa-VIP(1-28) and Ro25-1553) mimicked PACAP38/VIP-induced glycerol release, while the VPAC2 antagonist PG99-465 right-shifted dose-response curves; PAC1-R and VPAC1-R antagonists/agonists had no effect on lipolysis, demonstrating VPAC2 as the sole mediator.","method":"RT-PCR for receptor expression; glycerol release assay with selective agonists (Ro25-1553, Hexa-VIP) and antagonists (PACAP(6-38), PG97-269, PG99-465) in primary rat adipocytes","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — selective pharmacological dissection with multiple subtype-selective ligands and functional lipolysis assay","pmids":["15514088"],"is_preprint":false},{"year":2009,"finding":"VIP acting via VPAC2 receptors is trophic for proliferating postnatal nestin-positive dentate neural stem/progenitor cells (NSPCs) and shifts the fate of symmetrically dividing NSPCs toward a nestin-only phenotype; selective VPAC1 activation instead directs NSPCs toward granule cell neurogenesis; Vipr2-/- mice show reduced progeny survival and dentate neurogenesis with a specific reduction of type 2 nestin-positive precursors in vivo.","method":"Selective receptor agonists on postnatal dentate NSPCs; BrdU/immunofluorescence; Vipr2-/- mouse in vivo analysis of neurogenesis","journal":"Stem cells","confidence":"High","confidence_rationale":"Tier 2 / Strong — differential pharmacology plus KO with in vivo and in vitro orthogonal readouts","pmids":["19650041"],"is_preprint":false},{"year":2005,"finding":"VIP enhances hippocampal CA1 synaptic transmission via both VPAC1 and VPAC2 receptors; VPAC2-mediated actions are specifically dependent on PKA activity (blocked by H-89 but not GF109203X), whereas VPAC1-mediated actions require PKC activity.","method":"Extracellular field potential recording in rat hippocampal slices; selective VPAC2 agonist RO 25-1553 and antagonist PG 99-465; PKA inhibitor H-89 and PKC inhibitor GF109203X","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — selective pharmacology with defined signaling pathway inhibitors, single lab","pmids":["15935995"],"is_preprint":false},{"year":2005,"finding":"VPAC2 receptor activation in the spinal cord contributes to p38 MAP kinase phosphorylation and behavioral reflex sensitization in neuropathic pain: a VPAC2 agonist enhanced p38 phosphorylation and caused behavioral sensitization in naïve animals, blocked by a p38 inhibitor; NMDA/VPAC2/NK2 receptor antagonists and the glial inhibitor propentofylline all reduced p38/p42/44 activation after nerve injury.","method":"Intrathecal VPAC2 agonist/antagonist administration; p38 and p42/44 phosphorylation assays; behavioral nociceptive tests in nerve constriction injury model","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo pharmacological experiments with defined signaling readouts, single lab","pmids":["16202621"],"is_preprint":false},{"year":2006,"finding":"VPAC2 receptor in porcine basilar arteries is located in the outer smooth muscle layers and mediates neurally-evoked (electrical stimulation at 20 Hz) vasodilation independently of nitric oxide synthase and the endothelium; VPAC2 antagonist PG-99-465 attenuated the vasodilatory response to electrical stimulation.","method":"Immunocytochemistry for receptor localization; pharmacological vasodilation assays with L-NAME, endothelial denudation, and selective VPAC2 antagonist/agonist in porcine basilar artery preparations; RT-PCR","journal":"Journal of cerebral blood flow and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor localization by immunocytochemistry plus functional pharmacological dissection with selective compounds, single lab","pmids":["15959462"],"is_preprint":false},{"year":2005,"finding":"VPAC2 receptor activation in SCN neurons enhances the hyperpolarization-activated mixed cation current (Ih) via cAMP, causing membrane depolarization of thalamocortical relay neurons and attenuation of intrathalamic rhythmic activities; these effects are absent in Vipr2-/- mice.","method":"Intracellular recordings in thalamic slices from wild-type and Vipr2-/- mice; VIP and PACAP application; pharmacological cAMP manipulation","journal":"Journal of neurophysiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mice with electrophysiological characterization of ionic mechanism (Ih) and cAMP pathway, multiple complementary experiments","pmids":["16641377"],"is_preprint":false},{"year":2009,"finding":"VPAC2 receptor activation in the subparaventricular zone (SPZ) mediates both postsynaptic depolarization via a nonselective cationic conductance and presynaptic enhancement of GABA release from SCN terminals; these effects are mimicked by the selective VPAC2 agonist BAY 55-9837 and partially blocked by VIP(6-28).","method":"Patch-clamp recording in rat brain slices of SPZ; selective VPAC2 agonist BAY 55-9837; VIP receptor antagonist; TTX-resistant current measurements; mIPSC frequency analysis","journal":"Journal of neurophysiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — selective pharmacology with patch-clamp, pre- and postsynaptic mechanisms distinguished, single lab","pmids":["19571188"],"is_preprint":false},{"year":2009,"finding":"VPAC2 is the sole VIP/PACAP receptor expressed in MC3T3-E1 osteoblastic cells; PACAP/VIP stimulate cAMP accumulation and IL-6 release exclusively through VPAC2, and VPAC2 siRNA knockdown abolishes both responses; VPAC2-cAMP signaling suppresses osteoblastic differentiation (reduces alkaline phosphatase mRNA).","method":"RT-PCR; VPAC2 siRNA knockdown; cAMP assay; IL-6 ELISA; alkaline phosphatase mRNA quantification in MC3T3-E1 cells","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown confirms receptor identity plus functional readouts, single lab","pmids":["19496170"],"is_preprint":false},{"year":2011,"finding":"VPAC2 activation drives reactive astrocytosis: selective VPAC2 agonist Ro25-1553 induces reactive morphological changes in cultured astrocytes (polygonal to stellate) and increases cell surface expression of glutamate transporters GLAST and GLT-1; VPAC2 is transiently expressed in reactive astrocytes around brain injury sites in vivo.","method":"Cold injury brain lesion model in mice; immunohistochemistry; primary cultured astrocytes treated with dbcAMP and VPAC2 agonist; glutamate transporter surface expression assay","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — selective agonist with functional cellular readouts plus in vivo injury model, single lab","pmids":["21281617"],"is_preprint":false},{"year":2013,"finding":"Caveolin-1 is required for VPAC2 receptor internalization and desensitization in gastric smooth muscle: VIP stimulates tyrosine phosphorylation of caveolin-1 via Src kinase; disruption of caveolae by methyl-β-cyclodextrin, caveolin-1 siRNA knockdown, or caveolin-1 KO mice all significantly attenuate VPAC2 receptor internalization and desensitization.","method":"Methyl-β-cyclodextrin caveolae disruption; caveolin-1 siRNA; caveolin-1 KO mice; 125I-VIP binding; receptor biotinylation; adenylyl cyclase activity; muscle strip relaxation assays","journal":"Peptides","confidence":"High","confidence_rationale":"Tier 2 / Strong — three orthogonal approaches (pharmacological, siRNA, KO mouse) converge on same functional conclusion","pmids":["23499767"],"is_preprint":false},{"year":2005,"finding":"The VPAC2 receptor IC3 loop conserved residues are required for G-protein coupling and receptor regulation: L310 mutation reduces Gαs-coupled adenylyl cyclase efficacy by 75% without affecting Gα16-coupled Ca2+ signaling; R325 and K328 mutations reduce Ca2+ and cAMP responses; combined amino- and carboxy-terminal IC3 mutations generate a fully inactive receptor lacking phosphorylation and internalization, both of which are directly correlated with receptor activation efficacy.","method":"Point mutagenesis of IC3 loop residues; expression in CHO cells stably transfected with Gα16 and aequorin; adenylyl cyclase activity; Ca2+ measurement; receptor phosphorylation and internalization assays","journal":"Journal of molecular endocrinology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis with functional mechanistic readouts (cAMP, Ca2+, phosphorylation, internalization)","pmids":["15821106"],"is_preprint":false},{"year":2006,"finding":"The conserved Asn216 in TM3 of VPAC2 is important for receptor activation: N216Q mutation reduces VIP stimulation of adenylyl cyclase, receptor phosphorylation and internalization, indicating a role in G-protein activation analogous to the equivalent Asn229 in VPAC1.","method":"Conservative mutagenesis N216Q in VPAC2; adenylyl cyclase activity; receptor phosphorylation and internalization assays in CHO cells","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — single conservative mutation with functional assays, part of comparative study with VPAC1, single lab","pmids":["16650965"],"is_preprint":false},{"year":2001,"finding":"Conserved basic residues R172 and K179 in the second transmembrane helix of VPAC2 are required for receptor activation: R172 mutations reduce VIP potency by 20–500-fold; K179I mutation renders the receptor inactive to VIP; substituting Asp3 of VIP with Asn or Gln markedly improved potency at R172 mutants, suggesting R172 and VIP Asp3 come into close proximity in the active ligand-receptor complex.","method":"Site-directed mutagenesis (R172L, R172Q, K179Q, K179I); adenylyl cyclase assays with VIP and analogs; expressed in COS cells","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis with structure-activity analysis pointing to specific ligand-receptor contact, single lab","pmids":["11498510"],"is_preprint":false},{"year":1999,"finding":"Ligand selectivity of VPAC2 versus PAC1 receptors is determined primarily by the amino-terminal extracellular domain: chimeric receptor experiments show the N-terminal extracellular domain of each receptor determines VIP vs. PACAP-38 selectivity; substitution of increasing portions of VPAC2 sequence into a PAC1-N-terminal-domain chimera decreases VIP potency while increasing helodermin potency, indicating additional receptor domains differentially modulate VIP and helodermin (but not PACAP) binding.","method":"Construction and expression of VPAC2/PAC1 chimeric receptors in COS7 cells; 125I-PACAP-27 binding; cAMP assays with VIP, PACAP-38, PACAP-27, helodermin","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — domain-swap chimera approach with binding and functional assays, single lab","pmids":["10556928"],"is_preprint":false},{"year":1999,"finding":"The N-terminal extracellular domain of VPAC1 determines the selectivity of a VPAC1-selective agonist and antagonist; efficient receptor activation by selective VIP1 agonist additionally requires the first extracellular loop and distal VPAC1 receptor domains, as replacement of EC1 in VPAC1 by its VPAC2 counterpart markedly reduces maximal response.","method":"VPAC1/VPAC2 chimeric receptors evaluated for binding and functional activation in transfected cells","journal":"European journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — chimeric receptor domain mapping with binding and functional assays, relevant for defining VPAC2 structural specificity","pmids":["10491203"],"is_preprint":false},{"year":2000,"finding":"Alanine scanning of VIP identifies residues Thr11, Tyr22, and Asn28 as uniquely important for binding/activation of VPAC2 (vs. VPAC1): substitution of Thr11 and Asn28 selectively increases Ki for VPAC2 binding; substitution of Tyr22 selectively increases EC50 for VPAC2 adenylyl cyclase activation. Combining three mutations (Ala11,22,28) yields the first highly selective (>1000-fold) VPAC1 agonist.","method":"Solid-phase synthesis of alanine-scan VIP analogs; binding (Ki) and adenylyl cyclase activation (EC50) in cell membranes expressing recombinant VPAC1 or VPAC2; 3D molecular modeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic alanine scanning across all 28 residues with binding and functional assays, structural modeling, development of selective tools","pmids":["10801840"],"is_preprint":false},{"year":2007,"finding":"VPAC2 receptor VIPR2 transcription and cyclic-AMP signaling are significantly increased in cultured lymphocytes from schizophrenia patients with microduplications of 7q36.3 containing VIPR2, implicating increased VPAC2 signaling as the functional consequence of gene copy number gain.","method":"cAMP signaling assays and VIPR2 transcription measurement in cultured lymphocytes from patients with confirmed 7q36.3 microduplications versus controls","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct measurement of receptor expression and signaling in patient-derived cells, single study","pmids":["21346763"],"is_preprint":false},{"year":2019,"finding":"VIPR2 microduplication in a BAC transgenic mouse model recapitulates schizophrenia-related phenotypes: increased striatal cAMP/PKA signaling, disrupted early postnatal striatal development, dopamine D2 receptor abnormality, and cognitive/sensorimotor gating/social behavioral deficits; genetic removal of VIPR2 transgene in dopaminoceptive neurons (Drd1a-Cre) rescued D2 receptor abnormality and multiple behavioral deficits, implicating VIPR2 overexpression in dopaminoceptive neurons as pathogenic.","method":"Conditional VIPR2 BAC transgenic mouse; Drd1a-Cre intersectional rescue; cAMP/PKA signaling assays; dopamine D2 receptor measurement; behavioral testing","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional transgenic model with cell-type-specific genetic rescue, multiple molecular and behavioral readouts","pmids":["31444475"],"is_preprint":false},{"year":2020,"finding":"VIP/VPAC2-expressing cells together constitute a pacemaker hub in the SCN circuit: using intersectional genetics and real-time imaging, VIP-expressing and VPAC2-expressing cells are neurochemically and electrophysiologically distinct but together control de novo rhythmicity, setting ensemble period and phase with circuit-level spatiotemporal complexity.","method":"Intersectional genetics (VIP-Cre and VPAC2 reporter mice); real-time bioluminescence imaging; electrophysiology of defined cell populations","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — intersectional genetic dissection with real-time imaging of molecular clock, defines circuit-level function","pmids":["32636383"],"is_preprint":false},{"year":2020,"finding":"VPAC2-expressing cells contribute autonomously to SCN timekeeping: lengthening the intrinsic TTFL period of VPAC2-expressing cells (by CK1ε deletion) lengthens behavioral circadian period; abrogation of circadian competence in VPAC2 cells (Bmal1 deletion) severely disrupts circadian behavioral rhythms and SCN TTFL timekeeping, demonstrating that VPAC2-expressing cells are a functionally powerful subset within the SCN circuit.","method":"Intersectional genetics in VPAC2-Cre mice: cell-type-specific deletion of CK1ε and Bmal1; wheel-running behavior; bioluminescent TTFL imaging in SCN slices","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific genetic manipulation with behavioral and molecular phenotypes, orthogonal to VIP-cell manipulation studies","pmids":["33234609"],"is_preprint":false},{"year":2020,"finding":"VPAC2 receptor activation impairs neurite outgrowth in cortical neurons via a PKA-dependent mechanism: VIP and the VPAC2-selective agonist Ro25-1553 reduced total numbers and lengths of dendrites and axons; these effects were blocked by the VPAC2 antagonist PG99-465, absent in Vipr2-/- neurons, and blocked by the PKA inhibitor H-89 but not by PKC or MEK inhibitors.","method":"Primary mouse cortical neuron cultures; selective agonist Ro25-1553 and antagonist PG99-465; Vipr2-/- neurons; PKA (H-89), PKC (GF109203X), and MEK (U0126) inhibitors; neurite morphometry","journal":"Frontiers in neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO neurons plus pharmacological pathway dissection, multiple inhibitors confirm PKA specificity","pmids":["32581681"],"is_preprint":false},{"year":2020,"finding":"Loss of VIPR2 function in mice causes myopia: Vipr2-KO mice show significant myopic refraction shift; VIPR2 is expressed in retinal bipolar cells; VIPR2 agonist Ro25-1553 inhibited form deprivation myopia, while antagonist PG99-465 induced relative myopia; Vipr2-KO mice show enlarged b-wave amplitudes consistent with altered bipolar cell function.","method":"Vipr2-KO mice; retinal single-cell transcriptome sequencing for cell-type expression; pharmacological agonist/antagonist administration; electroretinography; refraction measurement","journal":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO model plus single-cell expression data plus pharmacological rescue/induction with cell-type-specific physiological readout (ERG)","pmids":["33318135"],"is_preprint":false},{"year":2022,"finding":"VIP-VIPR2 signaling controls tumor cell migration via PI3Kγ-mediated synthesis of PI(3,4,5)P3, which promotes membrane localization of WAVE2 and Rac-mediated actin nucleation for lamellipodium formation: VIPR2 co-localizes with WAVE2 at lamellipodia; VIPR2 silencing suppresses VIP-induced migration and lamellipodium extension; PI3Kγ inhibitor blocks VIPR2-overexpressing cell migration; VIPR2 knockdown reduces WAVE2-ARP3-actin interactions.","method":"VIPR2 siRNA silencing and stable overexpression in MDA-MB-231 and MCF-7 cells; PI3K activity assay; PI(3,4,5)P3 membrane localization imaging; WAVE2-ARP3-actin co-IP; PI3Kγ inhibitor; wound healing/migration assay","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (knockdown, overexpression, co-IP, lipid imaging) in single lab","pmids":["36237322"],"is_preprint":false},{"year":2003,"finding":"VPAC2 receptor is expressed by immature pancreatic epithelial cells between embryonic days 12–16 and mediates VIP/PACAP-induced survival, proliferation, and increased endocrine cell number in embryonic pancreas in vitro.","method":"Embryonic pancreas organ culture with VIP/PACAP; RT-PCR for VPAC2 expression during development; cell survival and proliferation assays; endocrine cell counting","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor expression timing correlated with functional response in organ culture, single lab","pmids":["12502497"],"is_preprint":false},{"year":2014,"finding":"VPAC2 receptor deficiency in mice exacerbates EAE: Vipr2-/- mice show enhanced neuroinflammation, increased Th1/Th17 cytokines (IFN-γ, IL-17), reduced anti-inflammatory cytokines (IL-10, TGFβ, IL-4), and strikingly reduced abundance and proliferative index of CD4+CD25+FoxP3+ Tregs in lymph nodes, thymus, and CNS; in vitro suppressive activity of Tregs from VPAC2-deficient mice is impaired.","method":"Vipr2-/- mice in MOG35-55 EAE model; histopathology; cytokine measurement (ELISA/flow); Treg frequency by FACS; in vitro Treg suppression assay","journal":"Brain, behavior, and immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO model with multiple immune readouts and direct functional Treg assay, mechanistic pathway placement","pmids":["25305591"],"is_preprint":false},{"year":2017,"finding":"VPAC2 receptor deficiency impairs extinction of cued fear memory and alters dendritic morphology in the prelimbic and infralimbic cortices: Vipr2-/- mice show normal fear acquisition and expression but impaired cued fear extinction; prelimbic cortex neurons show reduced cell body size and reduced total dendritic branch number and length; proximal dendritic material in infralimbic cortex is increased in Vipr2-/- mice.","method":"Pavlovian fear conditioning and extinction in Vipr2-/- and wild-type mice; Golgi staining and morphological analysis of PrL and IL cortex neurons; Sholl analysis","journal":"Neurobiology of learning and memory","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO model with behavioral and morphological phenotypes, two brain regions analyzed, single lab","pmids":["29030297"],"is_preprint":false},{"year":2007,"finding":"VPAC2 receptor stimulation inhibits HIV-1 integration into host DNA: daily VPAC2 agonist treatment (but not VPAC1 or PAC1 agonists) caused up to 90% inhibition of HIV-1 productive infection in cell lines and PBMCs without affecting cell surface co-receptors, apoptosis, viral entry, or reverse transcription, implicating the integration step as the target.","method":"VPAC2/VPAC1/PAC1-selective agonist treatment of cell lines and PBMCs; HIV-1 infection assays; entry/reverse transcription/integration assays","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — step-specific HIV infection assays with receptor subtype-selective compounds, single lab","pmids":["17257640"],"is_preprint":false},{"year":2015,"finding":"Postnatal overactivation of VPAC2 receptor (Ro 25-1553, P1–P14) reduces synaptophysin and PSD-95 protein levels specifically in the prefrontal cortex (not hippocampus) and disrupts prepulse inhibition of acoustic startle in adult mice, modeling the developmental consequences of VIPR2 overdosage.","method":"Postnatal subcutaneous Ro 25-1553 in C57BL/6 mice; Western blot for synaptic proteins; PPI of acoustic startle; open field; social interaction; fear conditioning","journal":"Psychopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — selective agonist with regional protein and behavioral readouts, single lab","pmids":["25575489"],"is_preprint":false},{"year":1999,"finding":"The human VIPR2 gene spans 117 kb, is encoded by 13 exons, with the initiator codon in exon 1, the stop codon and poly-adenylation signal in exon 13, an 80% GC-rich 5' UTR, intron sizes ranging from 68 bp to 45 kb, and maps to chromosome 7q36.3.","method":"Gene structure characterization from genomic clones; exon-intron boundary sequencing; promoter region analysis","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genomic characterization, single lab, establishes gene structure","pmids":["10481065"],"is_preprint":false},{"year":2006,"finding":"A short-deletion (SD) splice variant of mouse VPAC2 lacking 14 amino acids at the end of the last transmembrane domain binds VIP with similar affinity to wild-type VPAC2 but lacks signaling capacity for adenylyl cyclase; cotransfection of SD and wild-type VPAC2 diminishes VIP enhancement of IL-4 production by preventing nuclear accumulation of c-Maf and JunB.","method":"Transfection of WT and SD VPAC2 constructs in Th2 cell line; IL-4 measurement; nuclear transcription factor level assays; endogenous VIP neutralization","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional comparison of natural splice variant vs. wild-type with molecular signaling readouts, single lab","pmids":["16709822"],"is_preprint":false}],"current_model":"VIPR2/VPAC2 is a Gs-coupled class B GPCR that, upon activation by VIP or PACAP, primarily signals through cAMP/PKA to regulate circadian clock synchronization in the SCN (where it is essential for intercellular coupling of molecular oscillators and photic gating), immune T cell Th2/Th1 balance (via c-Maf/JunB-dependent IL-4/IL-5 production), lipolysis, hippocampal and thalamic synaptic transmission, gastrointestinal smooth muscle relaxation (subject to GRK2-mediated homologous desensitization augmented by PKA and cross-regulated by M3-PKC-RKIP), and tumor cell migration (via PI3Kγ-WAVE2-actin); it localizes to the plasma membrane and additionally to primary cilia via a C-terminal RDYR targeting signal dependent on the BBSome; VIPR2 gene copy number gains increase receptor expression and cAMP signaling in patient lymphocytes and in BAC transgenic mice drive schizophrenia-related dopaminergic, cognitive, and developmental deficits."},"narrative":{"mechanistic_narrative":"VIPR2 (VPAC2) is a Gs-coupled class B receptor for the neuropeptides VIP and PACAP that, through cAMP/PKA signaling, governs intercellular coupling of the suprachiasmatic nucleus (SCN) circadian pacemaker and a broad set of neural, immune, and metabolic processes [PMID:12086606, PMID:16641377]. In the SCN it is essential for sustained behavioral and molecular clock rhythms: Vipr2-null mice fail to maintain rest/activity rhythms, lose circadian clock-gene expression, lose the bulk of VIP-evoked SCN electrophysiological responses, and exhibit desynchronized, low-amplitude single-cell oscillations [PMID:12086606, PMID:12542655, PMID:18554318], while gain of VPAC2 expression shortens period and accelerates re-entrainment [PMID:11027354]. VPAC2-expressing cells form a functionally powerful pacemaker subset whose intrinsic clock and circadian competence set ensemble period and phase [PMID:32636383, PMID:33234609], and VPAC2 signaling also gates photic input to the pacemaker [PMID:15071099]. In immunity, VIP-VPAC2 signaling maintains the Th2/Th1 cytokine balance by inducing the transcription factors c-Maf and JunB to drive IL-4/IL-5 production, and supports regulatory T cell abundance and function [PMID:11698667, PMID:15187104, PMID:25305591]. The receptor couples to cAMP/PKA but also engages cAMP-independent, PKC-dependent (neuroprotection) and PI3Kγ-WAVE2-actin (tumor cell migration) outputs, and mediates lipolysis, thalamic and hippocampal synaptic modulation, neurite/neurogenesis control, and vasodilation [PMID:15872042, PMID:36237322, PMID:15514088, PMID:16641377, PMID:15935995, PMID:19650041, PMID:15959462]. Receptor activity is shaped by IC3-loop and transmembrane residues required for G-protein coupling [PMID:15821106, PMID:11498510], by ligand-selectivity determinants in the N-terminal ectodomain [PMID:10556928, PMID:10801840], and by homologous desensitization via GRK2 phosphorylation—augmented by PKA, cross-inhibited by M3/PKC/RKIP, and dependent on caveolin-1 [PMID:18077607, PMID:17170028, PMID:23499767]. VPAC2 traffics to the plasma membrane and to primary cilia via a C-terminal RDYR signal recognized by Tubby, the BBSome, and Arl6 [PMID:23862016]. VIPR2 copy-number gain at 7q36.3 increases receptor transcription and cAMP signaling in patient lymphocytes and, in BAC transgenic mice acting through dopaminoceptive neurons, drives schizophrenia-related developmental, dopaminergic, and behavioral deficits [PMID:21346763, PMID:31444475].","teleology":[{"year":1999,"claim":"Establishing the gene's structure and ligand-selectivity architecture was the prerequisite for understanding how VPAC2 discriminates VIP from PACAP and where it sits in the genome.","evidence":"Genomic clone characterization mapping VIPR2 to 7q36.3, plus VPAC2/PAC1 and VPAC1/VPAC2 chimeric receptor binding/cAMP assays","pmids":["10481065","10556928","10491203"],"confidence":"Medium","gaps":["No structural model of the active ligand-receptor complex","Selectivity mapped by domain swaps without residue-level resolution in these studies"]},{"year":2000,"claim":"Defining the ligand and receptor residues that govern VPAC2 binding and activation answered how the receptor is selectively engaged and enabled selective pharmacological tools.","evidence":"Alanine scanning of VIP and IC3/transmembrane mutagenesis (R172, K179, N216, IC3 residues) with binding, cAMP, Ca2+, phosphorylation and internalization assays in heterologous cells","pmids":["10801840","11498510","16650965","15821106"],"confidence":"High","gaps":["No co-crystal/cryo-EM structure","Coupling to non-Gs pathways at residue level incompletely mapped"]},{"year":2002,"claim":"Knockout of Vipr2 answered whether the receptor is required for the circadian clock, establishing it as essential for sustained SCN rhythmicity and clock-gene expression.","evidence":"Vipr2-null mice with behavioral monitoring and SCN clock-gene in situ/Northern analysis","pmids":["12086606"],"confidence":"High","gaps":["Did not resolve single-cell versus circuit-level requirement","Mechanism of intercellular coupling not defined here"]},{"year":2003,"claim":"Electrophysiology in null and antagonist-treated slices answered whether VPAC2 mediates VIP's acute neuronal actions and the firing-rate rhythm, establishing a cellular basis for its clock role.","evidence":"SCN slice recording from Vipr2-/- and wild-type mice with selective VPAC2 agonist/antagonist","pmids":["12542655"],"confidence":"High","gaps":["Did not link firing changes to molecular oscillator at single-cell level"]},{"year":2004,"claim":"These studies answered how VPAC2 controls clock function beyond rhythm maintenance — gating photic input — and how it shapes adaptive immunity by setting the Th2/Th1 balance via specific transcription factors.","evidence":"pERK/c-FOS immunohistochemistry under light pulses in Vipr2-/- SCN; transcription factor (c-Maf, JunB) analysis in CD4 T cells from transgenic/KO/WT mice","pmids":["15071099","15187104"],"confidence":"High","gaps":["Downstream effectors linking VPAC2-cAMP to ERK gating not defined","Direct cis-regulatory targets of c-Maf/JunB at IL-4/IL-5 not mapped here"]},{"year":2005,"claim":"Subtype-selective pharmacology and KO revealed VPAC2 uses divergent downstream pathways — cAMP-independent PKC for neuroprotection and PKA for synaptic enhancement — broadening the model beyond a single Gs-cAMP output.","evidence":"Vipr2-/- mice and selective agonists/antagonists with PKC/PKA inhibitors in excitotoxicity, hippocampal field recording, lipolysis and thalamic recording paradigms","pmids":["15872042","15935995","15514088","16641377","15821106","16709822"],"confidence":"High","gaps":["Molecular basis of cAMP-independent PKC coupling unresolved","Splice-variant dominant-negative mechanism shown only in transfection"]},{"year":2006,"claim":"Smooth-muscle studies answered how VPAC2 signaling is terminated and cross-regulated, defining GRK2-mediated homologous desensitization and its inhibition by M3/PKC/RKIP cross-talk.","evidence":"RKIP(S153A) and GRK2 mutant expression, co-IP, phosphorylation and internalization assays in smooth muscle cells","pmids":["17170028"],"confidence":"High","gaps":["Generalizability beyond gastric smooth muscle untested","In vivo relevance of cross-talk not demonstrated"]},{"year":2008,"claim":"PKA was shown to amplify GRK2-mediated desensitization and single-cell imaging confirmed VPAC2 is required for synchronous oscillator coupling, refining the desensitization and circadian-coupling models.","evidence":"GRK2(S685A) mutagenesis with cAMP/desensitization assays; Per1-GFP live confocal imaging in Vipr2-/- and antagonist-treated SCN slices","pmids":["18077607","18554318"],"confidence":"High","gaps":["Coupling mechanism (which signal synchronizes cells) not fully resolved"]},{"year":2013,"claim":"These studies answered where VPAC2 is trafficked and how its surface behavior is modulated, defining ciliary targeting via an RDYR/BBSome pathway, caveolin-1-dependent internalization, and RAMP interactions.","evidence":"C-terminal/RDYR mutagenesis with Tubby/BBSome/Arl6 knockdown and ciliary imaging; caveolin-1 siRNA/KO and RAMP co-transfection with surface expression and G-protein assays","pmids":["23862016","23499767","22946657"],"confidence":"High","gaps":["Functional consequence of ciliary versus plasma-membrane signaling not resolved","RAMP modulation shown only in heterologous cells"]},{"year":2019,"claim":"Patient lymphocyte and BAC transgenic studies answered whether VIPR2 copy-number gain is causally pathogenic, establishing increased VPAC2-cAMP signaling in dopaminoceptive neurons as the disease-relevant mechanism.","evidence":"cAMP/transcription assays in patient lymphocytes; conditional VIPR2 BAC transgenic mouse with Drd1a-Cre intersectional rescue and behavioral/dopaminergic readouts","pmids":["21346763","31444475","25575489"],"confidence":"High","gaps":["Mechanism linking elevated cAMP to D2 receptor abnormality unresolved","Human causal evidence remains correlative at cellular level"]},{"year":2020,"claim":"Intersectional genetics resolved VPAC2-expressing cells as an autonomous, functionally powerful pacemaker subset, and additional KO studies extended VPAC2's roles to neurite outgrowth and refractive (myopia) control.","evidence":"VPAC2-Cre cell-type-specific CK1ε/Bmal1 deletion with behavior and TTFL imaging; cortical neuron neurite assays with PKA dissection; Vipr2-KO with retinal scRNA-seq, ERG and refraction","pmids":["32636383","33234609","32581681","33318135"],"confidence":"High","gaps":["How VPAC2-cell intrinsic clock entrains the broader circuit not fully defined","Bipolar-cell signaling pathway to refractive development unmapped"]},{"year":2022,"claim":"Tumor cell studies answered how VPAC2 drives migration, defining a PI3Kγ-PIP3-WAVE2-Rac-actin pathway distinct from canonical cAMP signaling.","evidence":"VIPR2 silencing/overexpression with PI3K activity, PIP3 imaging, WAVE2-ARP3-actin co-IP and migration assays in breast cancer cells","pmids":["36237322"],"confidence":"Medium","gaps":["G-protein link between VPAC2 and PI3Kγ not defined","Single cell-line context, in vivo metastasis untested"]},{"year":null,"claim":"How VPAC2 selects among its divergent effector pathways (Gs-cAMP/PKA, PKC, PI3Kγ) in a tissue- and ligand-specific manner, and the structural basis of biased signaling and ciliary versus surface function, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No active-state structure of VPAC2","Determinants of pathway bias across tissues unknown","Functional role of ciliary localization in vivo undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,20,25]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[13,24,37]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[20,25,9]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[0,11,34]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,5,39]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,20,21]}],"complexes":[],"partners":["VIP","PACAP","GRK2","RKIP","CAV1","RAMP1","RAMP2","RAMP3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P41587","full_name":"Vasoactive intestinal polypeptide receptor 2","aliases":["Helodermin-preferring VIP receptor","Pituitary adenylate cyclase-activating polypeptide type III receptor","PACAP type III receptor","PACAP-R-3","PACAP-R3","VPAC2 receptor","VPAC2R"],"length_aa":438,"mass_kda":49.5,"function":"G protein-coupled receptor activated by the neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (ADCYAP1/PACAP) (PubMed:7811244, PubMed:35477937, PubMed:8933357). Binds VIP and both PACAP27 and PACAP38 bioactive peptides with the following order of potency PACAP38 = VIP > PACAP27 (PubMed:35477937, PubMed:8933357). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors. Activates cAMP-dependent pathway (PubMed:7811244, PubMed:35477937, PubMed:8933357). May be coupled to phospholipase C","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P41587/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VIPR2","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/VIPR2","total_profiled":1310},"omim":[{"mim_id":"613959","title":"SCHIZOPHRENIA 16; SCZD16","url":"https://www.omim.org/entry/613959"},{"mim_id":"605330","title":"INTERLEUKIN 22; IL22","url":"https://www.omim.org/entry/605330"},{"mim_id":"601970","title":"VASOACTIVE INTESTINAL PEPTIDE RECEPTOR 2; VIPR2","url":"https://www.omim.org/entry/601970"},{"mim_id":"181500","title":"SCHIZOPHRENIA; SCZD","url":"https://www.omim.org/entry/181500"},{"mim_id":"147850","title":"INTERLEUKIN 5; IL5","url":"https://www.omim.org/entry/147850"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Focal adhesion sites","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/VIPR2"},"hgnc":{"alias_symbol":["VPAC2","VPAC2R"],"prev_symbol":[]},"alphafold":{"accession":"P41587","domains":[{"cath_id":"4.10.1240.10","chopping":"22-108","consensus_level":"high","plddt":80.9749,"start":22,"end":108},{"cath_id":"1.20.1070.10","chopping":"113-182_195-311_320-386","consensus_level":"high","plddt":82.2473,"start":113,"end":386}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P41587","model_url":"https://alphafold.ebi.ac.uk/files/AF-P41587-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P41587-F1-predicted_aligned_error_v6.png","plddt_mean":74.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VIPR2","jax_strain_url":"https://www.jax.org/strain/search?query=VIPR2"},"sequence":{"accession":"P41587","fasta_url":"https://rest.uniprot.org/uniprotkb/P41587.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P41587/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P41587"}},"corpus_meta":[{"pmid":"12086606","id":"PMC_12086606","title":"The VPAC(2) receptor is essential for circadian function in the mouse suprachiasmatic nuclei.","date":"2002","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/12086606","citation_count":461,"is_preprint":false},{"pmid":"21285140","id":"PMC_21285140","title":"Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications.","date":"2011","source":"The American journal of psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/21285140","citation_count":357,"is_preprint":false},{"pmid":"21346763","id":"PMC_21346763","title":"Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia.","date":"2011","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/21346763","citation_count":261,"is_preprint":false},{"pmid":"15282712","id":"PMC_15282712","title":"Distribution of vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide receptors (VPAC1, VPAC2, and PAC1 receptor) in the rat brain.","date":"2004","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/15282712","citation_count":162,"is_preprint":false},{"pmid":"10801840","id":"PMC_10801840","title":"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. 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enhancement of population spikes in the CA1 area of the hippocampus.","date":"2006","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/16888168","citation_count":14,"is_preprint":false},{"pmid":"16641377","id":"PMC_16641377","title":"Excitatory actions of vasoactive intestinal peptide on mouse thalamocortical neurons are mediated by VPAC2 receptors.","date":"2006","source":"Journal of neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/16641377","citation_count":14,"is_preprint":false},{"pmid":"31444475","id":"PMC_31444475","title":"Dosage sensitivity intolerance of VIPR2 microduplication is disease causative to manifest schizophrenia-like phenotypes in a novel BAC transgenic mouse model.","date":"2019","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/31444475","citation_count":13,"is_preprint":false},{"pmid":"23499767","id":"PMC_23499767","title":"Caveolae-dependent internalization and homologous desensitization of VIP/PACAP receptor, VPAC₂, in gastrointestinal smooth muscle.","date":"2013","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/23499767","citation_count":12,"is_preprint":false},{"pmid":"31796800","id":"PMC_31796800","title":"The myopia susceptibility locus vasoactive intestinal peptide receptor 2 (VIPR2) contains variants with opposite effects.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31796800","citation_count":12,"is_preprint":false},{"pmid":"17257640","id":"PMC_17257640","title":"HIV-1 integration is inhibited by stimulation of the VPAC2 neuroendocrine receptor.","date":"2007","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/17257640","citation_count":12,"is_preprint":false},{"pmid":"21730107","id":"PMC_21730107","title":"The VPAC2 agonist peptide histidine isoleucine (PHI) up-regulates glutamate transport in the corpus callosum of a rat model of amyotrophic lateral sclerosis (hSOD1G93A) by inhibiting caspase-3 mediated inactivation of GLT-1a.","date":"2011","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/21730107","citation_count":12,"is_preprint":false},{"pmid":"16500728","id":"PMC_16500728","title":"Intein-mediated rapid purification and characterization of a novel recombinant agonist for VPAC2.","date":"2006","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/16500728","citation_count":12,"is_preprint":false},{"pmid":"36204104","id":"PMC_36204104","title":"Therapeutic potential of vasoactive intestinal peptide and its receptor VPAC2 in type 2 diabetes.","date":"2022","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/36204104","citation_count":11,"is_preprint":false},{"pmid":"15063009","id":"PMC_15063009","title":"Hexanoylation of a VPAC2 receptor-preferring ligand markedly increased its selectivity and potency.","date":"2004","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/15063009","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54136,"output_tokens":12042,"usd":0.171519,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":23425,"output_tokens":4724,"usd":0.117612,"stage2_stop_reason":"end_turn"},"total_usd":0.289131,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"VPAC2 receptor (encoded by Vipr2) is essential for circadian function in the mouse SCN: Vipr2-/- mice cannot sustain circadian rhythms of rest/activity behavior, fail to show circadian expression of core clock genes mPer1, mPer2, and mCry1 and the clock-controlled gene AVP in the SCN, and fail to show acute induction of mPer1 and mPer2 by nocturnal illumination.\",\n      \"method\": \"Vipr2 null mouse knockout; behavioral monitoring; clock gene expression analysis by in situ hybridization/Northern blot\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple defined molecular and behavioral phenotypes, highly cited and foundational study\",\n      \"pmids\": [\"12086606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"VPAC2 receptor is necessary for the major part of the electrophysiological actions of VIP on SCN neurons in vitro: fewer SCN cells from Vipr2-/- mice responded to VIP and the VPAC2-selective agonist Ro 25-1553; VIP-evoked responses in control SCN neurons were attenuated by the selective VPAC2 antagonist PG 99-465. Additionally, the midday peak in SCN electrical firing rate rhythm was lost in Vipr2-/- mice and mimicked in controls by chronic VPAC2 antagonist treatment.\",\n      \"method\": \"Electrophysiological recording of SCN neurons in brain slices from Vipr2-/- and wild-type mice; pharmacological blockade with selective VPAC2 agonist and antagonist\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mice plus pharmacological confirmation with selective agonist/antagonist, multiple orthogonal electrophysiological readouts\",\n      \"pmids\": [\"12542655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In Vipr2-/- mice, photic gating of input to the SCN is abolished: spontaneous circadian variation in pERK and c-FOS is absent, and light pulses given during both subjective day and subjective night robustly increase pERK and c-FOS (versus only subjective night in wild-type), indicating that VPAC2 signaling is required for temporal gating of photic input to the SCN circadian pacemaker.\",\n      \"method\": \"Immunohistochemical detection of pERK and c-FOS in Vipr2-/- and wild-type SCN under LD and DD conditions with light pulse experiments\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO model with two orthogonal molecular readouts (pERK, c-FOS), rigorously controlled under multiple lighting conditions\",\n      \"pmids\": [\"15071099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Overexpression of the human VPAC2 receptor in the SCN shortens the circadian period in constant darkness and accelerates resynchronization after an 8-h advance of the LD cycle, demonstrating that the level of VPAC2R expression directly influences the period and photic entrainment of the circadian clock.\",\n      \"method\": \"Transgenic mice overexpressing human VPAC2R from a YAC construct; wheel-running behavior monitoring in LD and constant darkness\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic gain-of-function model with quantitative behavioral phenotypes, complementary to null mutant data\",\n      \"pmids\": [\"11027354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Loss of VPAC2R in mice shifts T cell cytokine balance: VPAC2R-null mice show enhanced delayed-type hypersensitivity with increased IL-2 and IFN-γ (Th1 cytokines) and reduced IL-4 (Th2 cytokine) from splenic CD4+ T cells, and markedly lower IgE anti-hapten and cutaneous anaphylaxis, demonstrating that VIP-VPAC2R signaling normally maintains Th2/Th1 cytokine ratio.\",\n      \"method\": \"Vipr2-/- null mouse; hapten-evoked DTH assay; splenic CD4+ T cell cytokine production; serum Ig measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple immune readouts (DTH, anaphylaxis, cytokines, Ig), clearly mechanistic\",\n      \"pmids\": [\"11698667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"VIP binding to VPAC2 on CD4 T cells specifically induces up-regulation of the Th2-type transcription factors c-Maf and JunB (but not GATA3, T-bet, or NFATc), which leads to enhanced IL-4 and IL-5 production, establishing the molecular mechanism by which VPAC2 promotes Th2 differentiation.\",\n      \"method\": \"Analysis of transcription factor mRNA, protein and activity in TCR-stimulated CD4 T cells from VPAC2 transgenic, knockout, and wild-type mice; IL-4 and IL-5 measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgenic vs. KO comparison, multiple orthogonal readouts (mRNA, protein, activity), specific transcription factor identification\",\n      \"pmids\": [\"15187104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"VIP-VPAC2 signaling is required for SCN cellular rhythmicity: in Vipr2-/- mice, only a small minority of SCN cells exhibit circadian firing patterns; exogenous GRP can promote SCN cellular rhythms in Vipr2-/- slices via BB2 receptors, while BB2 receptor blockade in wild-type mice suppresses neuronal oscillations only when VPAC2 receptors are also blocked.\",\n      \"method\": \"Electrophysiological recording of individual SCN neurons in brain slices from Vipr2-/- and wild-type mice; pharmacological application of GRP and BB2/VPAC2 receptor antagonists\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO model plus pharmacological rescue with orthogonal neuropeptide, establishing pathway redundancy\",\n      \"pmids\": [\"16319315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"VPAC2R-null mice lacking a functional SCN clock retain strongly rhythmic hepatic clock gene expression (advanced in phase), entrained by food intake timing rather than light; both genotypes develop food-anticipatory activity rhythms under restricted feeding, demonstrating that VPAC2-dependent SCN function is not required for food-entrainable peripheral oscillator function.\",\n      \"method\": \"Vipr2-/- mice; wheel-running, corticosterone secretion, hepatic clock gene expression under normal and restricted feeding regimens\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO model with multiple physiological outputs and restricted feeding paradigm, clear epistatic placement of VPAC2 in light vs. food entrainment pathways\",\n      \"pmids\": [\"17442819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In Vipr2-/- mice and VIP-deficient mice, daily metabolic and feeding rhythms are advanced (peak in late day rather than early night) under LD conditions, and are abolished under constant light, demonstrating that VIP-VPAC2 signaling controls temporal organization of metabolism and feeding behavior.\",\n      \"method\": \"Metabolic monitoring (indirect calorimetry), feeding behavior, and wheel-running in Vipr2-/- and VIP-deficient mice under LD and constant light\",\n      \"journal\": \"American journal of physiology. Regulatory, integrative and comparative physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — parallel KO models with quantitative metabolic phenotypes confirm VPAC2 requirement for metabolic rhythm\",\n      \"pmids\": [\"18032467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In gastric smooth muscle, VPAC2 receptor desensitization is mediated exclusively by GRK2: VIP induces GRK2-mediated phosphorylation of VPAC2, followed by internalization and desensitization; PKA-mediated phosphorylation of GRK2 at Ser685 augments its kinase activity and Gβγ binding, enhancing VPAC2 receptor phosphorylation, internalization, and desensitization.\",\n      \"method\": \"Expression of kinase-deficient GRK2(K220R) and PKA-site deficient GRK2(S685A) mutants; PKA inhibitor (PKI); 125I-VIP binding; receptor biotinylation; adenylyl cyclase activity and cAMP assays in smooth muscle cells\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis of kinase and phosphorylation sites combined with functional desensitization assays, multiple orthogonal methods in smooth muscle system\",\n      \"pmids\": [\"18077607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Cross-regulation of VPAC2 receptor desensitization by M3 muscarinic receptors: ACh activation of M3 receptors inhibits GRK2-mediated VPAC2 receptor phosphorylation, internalization and desensitization via PKC-mediated phosphorylation of RKIP at Ser153, which causes RKIP to dissociate from Raf-1 and instead bind and inhibit GRK2. In muscle cells expressing RKIP(S153A), this cross-regulatory mechanism is abolished.\",\n      \"method\": \"PKC inhibitors; RKIP(S153A) mutant expression in smooth muscle cells; RKIP-GRK2 and RKIP-Raf association by co-IP; VPAC2 phosphorylation, internalization, ERK1/2 activity assays\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — phosphorylation-site mutagenesis, co-IP, and multiple functional assays establish the cross-talk mechanism\",\n      \"pmids\": [\"17170028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In individual SCN neurons from Vipr2-/- mice, fewer cells express detectable Per1-driven GFP rhythms, the oscillation amplitude is significantly lower, and cells are poorly synchronized with each other compared with wild-type; pharmacological VPAC2 receptor blockade in wild-type SCN partially mimics the Vipr2-/- phenotype, demonstrating that VPAC2 intercellular signaling is required for robust, synchronous clock gene oscillations at the single-cell level.\",\n      \"method\": \"Real-time confocal live imaging of destabilized GFP driven by Per1 in SCN-containing brain slices from Vipr2-/- and wild-type mice; VPAC2 pharmacological blockade\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live imaging with genetic KO and pharmacological confirmation, single-cell resolution\",\n      \"pmids\": [\"18554318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"VPAC2 receptor interacts physically with all three RAMPs (RAMP1, RAMP2, RAMP3), enhancing their cell surface expression; this VPAC2-RAMP interaction modulates G-protein coupling in an agonist-specific manner, though cAMP production is not affected.\",\n      \"method\": \"Co-transfection of VPAC2 with RAMPs in HEK293S and CHO-K1 cells; ELISA for cell-surface RAMP/receptor expression; GTPγS binding to Gs, Gi, G12, Gq; cAMP assays\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell surface ELISA and G-protein coupling assays in co-transfected cells, single lab but multiple readouts\",\n      \"pmids\": [\"22946657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"VPAC2 localizes to primary cilia in neurons and glial cells of multiple brain regions including the SCN and thalamus; the C-terminus of VPAC2 is both necessary and sufficient for ciliary targeting, with a tetrapeptide RDYR motif serving as the ciliary targeting signal; ciliary targeting requires Tubby, the BBSome, and the BBSome-targeting factor Arl6.\",\n      \"method\": \"Endogenous VPAC2 immunofluorescence in brain sections; C-terminus deletion/truncation constructs; RDYR motif mutagenesis; knockdown of Tubby, BBSome subunits, and Arl6\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis of targeting signal combined with genetic knockdown of targeting machinery and localization imaging\",\n      \"pmids\": [\"23862016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"VPAC2 receptors mediate the PKC-dependent neuroprotective effects of VIP against neonatal excitotoxic brain lesions: VIP effects were mimicked by VPAC2 agonists and PHI but not VPAC1 agonists or PACAP; neuroprotection was lost in Vipr2-/- mice; protection is independent of cAMP and mediated by protein kinase C.\",\n      \"method\": \"Vipr2-/- mice and pharmacological agonist/antagonist approach in the ibotenate neonatal excitotoxicity mouse model; in situ hybridization for VPAC2 mRNA; VIP-specific binding assays\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO combined with receptor subtype-selective pharmacology and mechanistic pathway dissection (cAMP-independent, PKC-dependent)\",\n      \"pmids\": [\"15872042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"VPAC2 receptor activation mediates lipolysis in primary rat adipocytes: VPAC2-selective agonists (Hexa-VIP(1-28) and Ro25-1553) mimicked PACAP38/VIP-induced glycerol release, while the VPAC2 antagonist PG99-465 right-shifted dose-response curves; PAC1-R and VPAC1-R antagonists/agonists had no effect on lipolysis, demonstrating VPAC2 as the sole mediator.\",\n      \"method\": \"RT-PCR for receptor expression; glycerol release assay with selective agonists (Ro25-1553, Hexa-VIP) and antagonists (PACAP(6-38), PG97-269, PG99-465) in primary rat adipocytes\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — selective pharmacological dissection with multiple subtype-selective ligands and functional lipolysis assay\",\n      \"pmids\": [\"15514088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"VIP acting via VPAC2 receptors is trophic for proliferating postnatal nestin-positive dentate neural stem/progenitor cells (NSPCs) and shifts the fate of symmetrically dividing NSPCs toward a nestin-only phenotype; selective VPAC1 activation instead directs NSPCs toward granule cell neurogenesis; Vipr2-/- mice show reduced progeny survival and dentate neurogenesis with a specific reduction of type 2 nestin-positive precursors in vivo.\",\n      \"method\": \"Selective receptor agonists on postnatal dentate NSPCs; BrdU/immunofluorescence; Vipr2-/- mouse in vivo analysis of neurogenesis\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — differential pharmacology plus KO with in vivo and in vitro orthogonal readouts\",\n      \"pmids\": [\"19650041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"VIP enhances hippocampal CA1 synaptic transmission via both VPAC1 and VPAC2 receptors; VPAC2-mediated actions are specifically dependent on PKA activity (blocked by H-89 but not GF109203X), whereas VPAC1-mediated actions require PKC activity.\",\n      \"method\": \"Extracellular field potential recording in rat hippocampal slices; selective VPAC2 agonist RO 25-1553 and antagonist PG 99-465; PKA inhibitor H-89 and PKC inhibitor GF109203X\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — selective pharmacology with defined signaling pathway inhibitors, single lab\",\n      \"pmids\": [\"15935995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"VPAC2 receptor activation in the spinal cord contributes to p38 MAP kinase phosphorylation and behavioral reflex sensitization in neuropathic pain: a VPAC2 agonist enhanced p38 phosphorylation and caused behavioral sensitization in naïve animals, blocked by a p38 inhibitor; NMDA/VPAC2/NK2 receptor antagonists and the glial inhibitor propentofylline all reduced p38/p42/44 activation after nerve injury.\",\n      \"method\": \"Intrathecal VPAC2 agonist/antagonist administration; p38 and p42/44 phosphorylation assays; behavioral nociceptive tests in nerve constriction injury model\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo pharmacological experiments with defined signaling readouts, single lab\",\n      \"pmids\": [\"16202621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"VPAC2 receptor in porcine basilar arteries is located in the outer smooth muscle layers and mediates neurally-evoked (electrical stimulation at 20 Hz) vasodilation independently of nitric oxide synthase and the endothelium; VPAC2 antagonist PG-99-465 attenuated the vasodilatory response to electrical stimulation.\",\n      \"method\": \"Immunocytochemistry for receptor localization; pharmacological vasodilation assays with L-NAME, endothelial denudation, and selective VPAC2 antagonist/agonist in porcine basilar artery preparations; RT-PCR\",\n      \"journal\": \"Journal of cerebral blood flow and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor localization by immunocytochemistry plus functional pharmacological dissection with selective compounds, single lab\",\n      \"pmids\": [\"15959462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"VPAC2 receptor activation in SCN neurons enhances the hyperpolarization-activated mixed cation current (Ih) via cAMP, causing membrane depolarization of thalamocortical relay neurons and attenuation of intrathalamic rhythmic activities; these effects are absent in Vipr2-/- mice.\",\n      \"method\": \"Intracellular recordings in thalamic slices from wild-type and Vipr2-/- mice; VIP and PACAP application; pharmacological cAMP manipulation\",\n      \"journal\": \"Journal of neurophysiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mice with electrophysiological characterization of ionic mechanism (Ih) and cAMP pathway, multiple complementary experiments\",\n      \"pmids\": [\"16641377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"VPAC2 receptor activation in the subparaventricular zone (SPZ) mediates both postsynaptic depolarization via a nonselective cationic conductance and presynaptic enhancement of GABA release from SCN terminals; these effects are mimicked by the selective VPAC2 agonist BAY 55-9837 and partially blocked by VIP(6-28).\",\n      \"method\": \"Patch-clamp recording in rat brain slices of SPZ; selective VPAC2 agonist BAY 55-9837; VIP receptor antagonist; TTX-resistant current measurements; mIPSC frequency analysis\",\n      \"journal\": \"Journal of neurophysiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — selective pharmacology with patch-clamp, pre- and postsynaptic mechanisms distinguished, single lab\",\n      \"pmids\": [\"19571188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"VPAC2 is the sole VIP/PACAP receptor expressed in MC3T3-E1 osteoblastic cells; PACAP/VIP stimulate cAMP accumulation and IL-6 release exclusively through VPAC2, and VPAC2 siRNA knockdown abolishes both responses; VPAC2-cAMP signaling suppresses osteoblastic differentiation (reduces alkaline phosphatase mRNA).\",\n      \"method\": \"RT-PCR; VPAC2 siRNA knockdown; cAMP assay; IL-6 ELISA; alkaline phosphatase mRNA quantification in MC3T3-E1 cells\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown confirms receptor identity plus functional readouts, single lab\",\n      \"pmids\": [\"19496170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"VPAC2 activation drives reactive astrocytosis: selective VPAC2 agonist Ro25-1553 induces reactive morphological changes in cultured astrocytes (polygonal to stellate) and increases cell surface expression of glutamate transporters GLAST and GLT-1; VPAC2 is transiently expressed in reactive astrocytes around brain injury sites in vivo.\",\n      \"method\": \"Cold injury brain lesion model in mice; immunohistochemistry; primary cultured astrocytes treated with dbcAMP and VPAC2 agonist; glutamate transporter surface expression assay\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — selective agonist with functional cellular readouts plus in vivo injury model, single lab\",\n      \"pmids\": [\"21281617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Caveolin-1 is required for VPAC2 receptor internalization and desensitization in gastric smooth muscle: VIP stimulates tyrosine phosphorylation of caveolin-1 via Src kinase; disruption of caveolae by methyl-β-cyclodextrin, caveolin-1 siRNA knockdown, or caveolin-1 KO mice all significantly attenuate VPAC2 receptor internalization and desensitization.\",\n      \"method\": \"Methyl-β-cyclodextrin caveolae disruption; caveolin-1 siRNA; caveolin-1 KO mice; 125I-VIP binding; receptor biotinylation; adenylyl cyclase activity; muscle strip relaxation assays\",\n      \"journal\": \"Peptides\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three orthogonal approaches (pharmacological, siRNA, KO mouse) converge on same functional conclusion\",\n      \"pmids\": [\"23499767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The VPAC2 receptor IC3 loop conserved residues are required for G-protein coupling and receptor regulation: L310 mutation reduces Gαs-coupled adenylyl cyclase efficacy by 75% without affecting Gα16-coupled Ca2+ signaling; R325 and K328 mutations reduce Ca2+ and cAMP responses; combined amino- and carboxy-terminal IC3 mutations generate a fully inactive receptor lacking phosphorylation and internalization, both of which are directly correlated with receptor activation efficacy.\",\n      \"method\": \"Point mutagenesis of IC3 loop residues; expression in CHO cells stably transfected with Gα16 and aequorin; adenylyl cyclase activity; Ca2+ measurement; receptor phosphorylation and internalization assays\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis with functional mechanistic readouts (cAMP, Ca2+, phosphorylation, internalization)\",\n      \"pmids\": [\"15821106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The conserved Asn216 in TM3 of VPAC2 is important for receptor activation: N216Q mutation reduces VIP stimulation of adenylyl cyclase, receptor phosphorylation and internalization, indicating a role in G-protein activation analogous to the equivalent Asn229 in VPAC1.\",\n      \"method\": \"Conservative mutagenesis N216Q in VPAC2; adenylyl cyclase activity; receptor phosphorylation and internalization assays in CHO cells\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — single conservative mutation with functional assays, part of comparative study with VPAC1, single lab\",\n      \"pmids\": [\"16650965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Conserved basic residues R172 and K179 in the second transmembrane helix of VPAC2 are required for receptor activation: R172 mutations reduce VIP potency by 20–500-fold; K179I mutation renders the receptor inactive to VIP; substituting Asp3 of VIP with Asn or Gln markedly improved potency at R172 mutants, suggesting R172 and VIP Asp3 come into close proximity in the active ligand-receptor complex.\",\n      \"method\": \"Site-directed mutagenesis (R172L, R172Q, K179Q, K179I); adenylyl cyclase assays with VIP and analogs; expressed in COS cells\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis with structure-activity analysis pointing to specific ligand-receptor contact, single lab\",\n      \"pmids\": [\"11498510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Ligand selectivity of VPAC2 versus PAC1 receptors is determined primarily by the amino-terminal extracellular domain: chimeric receptor experiments show the N-terminal extracellular domain of each receptor determines VIP vs. PACAP-38 selectivity; substitution of increasing portions of VPAC2 sequence into a PAC1-N-terminal-domain chimera decreases VIP potency while increasing helodermin potency, indicating additional receptor domains differentially modulate VIP and helodermin (but not PACAP) binding.\",\n      \"method\": \"Construction and expression of VPAC2/PAC1 chimeric receptors in COS7 cells; 125I-PACAP-27 binding; cAMP assays with VIP, PACAP-38, PACAP-27, helodermin\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — domain-swap chimera approach with binding and functional assays, single lab\",\n      \"pmids\": [\"10556928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The N-terminal extracellular domain of VPAC1 determines the selectivity of a VPAC1-selective agonist and antagonist; efficient receptor activation by selective VIP1 agonist additionally requires the first extracellular loop and distal VPAC1 receptor domains, as replacement of EC1 in VPAC1 by its VPAC2 counterpart markedly reduces maximal response.\",\n      \"method\": \"VPAC1/VPAC2 chimeric receptors evaluated for binding and functional activation in transfected cells\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — chimeric receptor domain mapping with binding and functional assays, relevant for defining VPAC2 structural specificity\",\n      \"pmids\": [\"10491203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Alanine scanning of VIP identifies residues Thr11, Tyr22, and Asn28 as uniquely important for binding/activation of VPAC2 (vs. VPAC1): substitution of Thr11 and Asn28 selectively increases Ki for VPAC2 binding; substitution of Tyr22 selectively increases EC50 for VPAC2 adenylyl cyclase activation. Combining three mutations (Ala11,22,28) yields the first highly selective (>1000-fold) VPAC1 agonist.\",\n      \"method\": \"Solid-phase synthesis of alanine-scan VIP analogs; binding (Ki) and adenylyl cyclase activation (EC50) in cell membranes expressing recombinant VPAC1 or VPAC2; 3D molecular modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic alanine scanning across all 28 residues with binding and functional assays, structural modeling, development of selective tools\",\n      \"pmids\": [\"10801840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"VPAC2 receptor VIPR2 transcription and cyclic-AMP signaling are significantly increased in cultured lymphocytes from schizophrenia patients with microduplications of 7q36.3 containing VIPR2, implicating increased VPAC2 signaling as the functional consequence of gene copy number gain.\",\n      \"method\": \"cAMP signaling assays and VIPR2 transcription measurement in cultured lymphocytes from patients with confirmed 7q36.3 microduplications versus controls\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct measurement of receptor expression and signaling in patient-derived cells, single study\",\n      \"pmids\": [\"21346763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VIPR2 microduplication in a BAC transgenic mouse model recapitulates schizophrenia-related phenotypes: increased striatal cAMP/PKA signaling, disrupted early postnatal striatal development, dopamine D2 receptor abnormality, and cognitive/sensorimotor gating/social behavioral deficits; genetic removal of VIPR2 transgene in dopaminoceptive neurons (Drd1a-Cre) rescued D2 receptor abnormality and multiple behavioral deficits, implicating VIPR2 overexpression in dopaminoceptive neurons as pathogenic.\",\n      \"method\": \"Conditional VIPR2 BAC transgenic mouse; Drd1a-Cre intersectional rescue; cAMP/PKA signaling assays; dopamine D2 receptor measurement; behavioral testing\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional transgenic model with cell-type-specific genetic rescue, multiple molecular and behavioral readouts\",\n      \"pmids\": [\"31444475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"VIP/VPAC2-expressing cells together constitute a pacemaker hub in the SCN circuit: using intersectional genetics and real-time imaging, VIP-expressing and VPAC2-expressing cells are neurochemically and electrophysiologically distinct but together control de novo rhythmicity, setting ensemble period and phase with circuit-level spatiotemporal complexity.\",\n      \"method\": \"Intersectional genetics (VIP-Cre and VPAC2 reporter mice); real-time bioluminescence imaging; electrophysiology of defined cell populations\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — intersectional genetic dissection with real-time imaging of molecular clock, defines circuit-level function\",\n      \"pmids\": [\"32636383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"VPAC2-expressing cells contribute autonomously to SCN timekeeping: lengthening the intrinsic TTFL period of VPAC2-expressing cells (by CK1ε deletion) lengthens behavioral circadian period; abrogation of circadian competence in VPAC2 cells (Bmal1 deletion) severely disrupts circadian behavioral rhythms and SCN TTFL timekeeping, demonstrating that VPAC2-expressing cells are a functionally powerful subset within the SCN circuit.\",\n      \"method\": \"Intersectional genetics in VPAC2-Cre mice: cell-type-specific deletion of CK1ε and Bmal1; wheel-running behavior; bioluminescent TTFL imaging in SCN slices\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific genetic manipulation with behavioral and molecular phenotypes, orthogonal to VIP-cell manipulation studies\",\n      \"pmids\": [\"33234609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"VPAC2 receptor activation impairs neurite outgrowth in cortical neurons via a PKA-dependent mechanism: VIP and the VPAC2-selective agonist Ro25-1553 reduced total numbers and lengths of dendrites and axons; these effects were blocked by the VPAC2 antagonist PG99-465, absent in Vipr2-/- neurons, and blocked by the PKA inhibitor H-89 but not by PKC or MEK inhibitors.\",\n      \"method\": \"Primary mouse cortical neuron cultures; selective agonist Ro25-1553 and antagonist PG99-465; Vipr2-/- neurons; PKA (H-89), PKC (GF109203X), and MEK (U0126) inhibitors; neurite morphometry\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO neurons plus pharmacological pathway dissection, multiple inhibitors confirm PKA specificity\",\n      \"pmids\": [\"32581681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of VIPR2 function in mice causes myopia: Vipr2-KO mice show significant myopic refraction shift; VIPR2 is expressed in retinal bipolar cells; VIPR2 agonist Ro25-1553 inhibited form deprivation myopia, while antagonist PG99-465 induced relative myopia; Vipr2-KO mice show enlarged b-wave amplitudes consistent with altered bipolar cell function.\",\n      \"method\": \"Vipr2-KO mice; retinal single-cell transcriptome sequencing for cell-type expression; pharmacological agonist/antagonist administration; electroretinography; refraction measurement\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO model plus single-cell expression data plus pharmacological rescue/induction with cell-type-specific physiological readout (ERG)\",\n      \"pmids\": [\"33318135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VIP-VIPR2 signaling controls tumor cell migration via PI3Kγ-mediated synthesis of PI(3,4,5)P3, which promotes membrane localization of WAVE2 and Rac-mediated actin nucleation for lamellipodium formation: VIPR2 co-localizes with WAVE2 at lamellipodia; VIPR2 silencing suppresses VIP-induced migration and lamellipodium extension; PI3Kγ inhibitor blocks VIPR2-overexpressing cell migration; VIPR2 knockdown reduces WAVE2-ARP3-actin interactions.\",\n      \"method\": \"VIPR2 siRNA silencing and stable overexpression in MDA-MB-231 and MCF-7 cells; PI3K activity assay; PI(3,4,5)P3 membrane localization imaging; WAVE2-ARP3-actin co-IP; PI3Kγ inhibitor; wound healing/migration assay\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (knockdown, overexpression, co-IP, lipid imaging) in single lab\",\n      \"pmids\": [\"36237322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"VPAC2 receptor is expressed by immature pancreatic epithelial cells between embryonic days 12–16 and mediates VIP/PACAP-induced survival, proliferation, and increased endocrine cell number in embryonic pancreas in vitro.\",\n      \"method\": \"Embryonic pancreas organ culture with VIP/PACAP; RT-PCR for VPAC2 expression during development; cell survival and proliferation assays; endocrine cell counting\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor expression timing correlated with functional response in organ culture, single lab\",\n      \"pmids\": [\"12502497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"VPAC2 receptor deficiency in mice exacerbates EAE: Vipr2-/- mice show enhanced neuroinflammation, increased Th1/Th17 cytokines (IFN-γ, IL-17), reduced anti-inflammatory cytokines (IL-10, TGFβ, IL-4), and strikingly reduced abundance and proliferative index of CD4+CD25+FoxP3+ Tregs in lymph nodes, thymus, and CNS; in vitro suppressive activity of Tregs from VPAC2-deficient mice is impaired.\",\n      \"method\": \"Vipr2-/- mice in MOG35-55 EAE model; histopathology; cytokine measurement (ELISA/flow); Treg frequency by FACS; in vitro Treg suppression assay\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO model with multiple immune readouts and direct functional Treg assay, mechanistic pathway placement\",\n      \"pmids\": [\"25305591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"VPAC2 receptor deficiency impairs extinction of cued fear memory and alters dendritic morphology in the prelimbic and infralimbic cortices: Vipr2-/- mice show normal fear acquisition and expression but impaired cued fear extinction; prelimbic cortex neurons show reduced cell body size and reduced total dendritic branch number and length; proximal dendritic material in infralimbic cortex is increased in Vipr2-/- mice.\",\n      \"method\": \"Pavlovian fear conditioning and extinction in Vipr2-/- and wild-type mice; Golgi staining and morphological analysis of PrL and IL cortex neurons; Sholl analysis\",\n      \"journal\": \"Neurobiology of learning and memory\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO model with behavioral and morphological phenotypes, two brain regions analyzed, single lab\",\n      \"pmids\": [\"29030297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"VPAC2 receptor stimulation inhibits HIV-1 integration into host DNA: daily VPAC2 agonist treatment (but not VPAC1 or PAC1 agonists) caused up to 90% inhibition of HIV-1 productive infection in cell lines and PBMCs without affecting cell surface co-receptors, apoptosis, viral entry, or reverse transcription, implicating the integration step as the target.\",\n      \"method\": \"VPAC2/VPAC1/PAC1-selective agonist treatment of cell lines and PBMCs; HIV-1 infection assays; entry/reverse transcription/integration assays\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — step-specific HIV infection assays with receptor subtype-selective compounds, single lab\",\n      \"pmids\": [\"17257640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Postnatal overactivation of VPAC2 receptor (Ro 25-1553, P1–P14) reduces synaptophysin and PSD-95 protein levels specifically in the prefrontal cortex (not hippocampus) and disrupts prepulse inhibition of acoustic startle in adult mice, modeling the developmental consequences of VIPR2 overdosage.\",\n      \"method\": \"Postnatal subcutaneous Ro 25-1553 in C57BL/6 mice; Western blot for synaptic proteins; PPI of acoustic startle; open field; social interaction; fear conditioning\",\n      \"journal\": \"Psychopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — selective agonist with regional protein and behavioral readouts, single lab\",\n      \"pmids\": [\"25575489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The human VIPR2 gene spans 117 kb, is encoded by 13 exons, with the initiator codon in exon 1, the stop codon and poly-adenylation signal in exon 13, an 80% GC-rich 5' UTR, intron sizes ranging from 68 bp to 45 kb, and maps to chromosome 7q36.3.\",\n      \"method\": \"Gene structure characterization from genomic clones; exon-intron boundary sequencing; promoter region analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genomic characterization, single lab, establishes gene structure\",\n      \"pmids\": [\"10481065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A short-deletion (SD) splice variant of mouse VPAC2 lacking 14 amino acids at the end of the last transmembrane domain binds VIP with similar affinity to wild-type VPAC2 but lacks signaling capacity for adenylyl cyclase; cotransfection of SD and wild-type VPAC2 diminishes VIP enhancement of IL-4 production by preventing nuclear accumulation of c-Maf and JunB.\",\n      \"method\": \"Transfection of WT and SD VPAC2 constructs in Th2 cell line; IL-4 measurement; nuclear transcription factor level assays; endogenous VIP neutralization\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional comparison of natural splice variant vs. wild-type with molecular signaling readouts, single lab\",\n      \"pmids\": [\"16709822\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VIPR2/VPAC2 is a Gs-coupled class B GPCR that, upon activation by VIP or PACAP, primarily signals through cAMP/PKA to regulate circadian clock synchronization in the SCN (where it is essential for intercellular coupling of molecular oscillators and photic gating), immune T cell Th2/Th1 balance (via c-Maf/JunB-dependent IL-4/IL-5 production), lipolysis, hippocampal and thalamic synaptic transmission, gastrointestinal smooth muscle relaxation (subject to GRK2-mediated homologous desensitization augmented by PKA and cross-regulated by M3-PKC-RKIP), and tumor cell migration (via PI3Kγ-WAVE2-actin); it localizes to the plasma membrane and additionally to primary cilia via a C-terminal RDYR targeting signal dependent on the BBSome; VIPR2 gene copy number gains increase receptor expression and cAMP signaling in patient lymphocytes and in BAC transgenic mice drive schizophrenia-related dopaminergic, cognitive, and developmental deficits.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VIPR2 (VPAC2) is a Gs-coupled class B receptor for the neuropeptides VIP and PACAP that, through cAMP/PKA signaling, governs intercellular coupling of the suprachiasmatic nucleus (SCN) circadian pacemaker and a broad set of neural, immune, and metabolic processes [#0, #20]. In the SCN it is essential for sustained behavioral and molecular clock rhythms: Vipr2-null mice fail to maintain rest/activity rhythms, lose circadian clock-gene expression, lose the bulk of VIP-evoked SCN electrophysiological responses, and exhibit desynchronized, low-amplitude single-cell oscillations [#0, #1, #11], while gain of VPAC2 expression shortens period and accelerates re-entrainment [#3]. VPAC2-expressing cells form a functionally powerful pacemaker subset whose intrinsic clock and circadian competence set ensemble period and phase [#33, #34], and VPAC2 signaling also gates photic input to the pacemaker [#2]. In immunity, VIP-VPAC2 signaling maintains the Th2/Th1 cytokine balance by inducing the transcription factors c-Maf and JunB to drive IL-4/IL-5 production, and supports regulatory T cell abundance and function [#4, #5, #39]. The receptor couples to cAMP/PKA but also engages cAMP-independent, PKC-dependent (neuroprotection) and PI3K\\u03b3-WAVE2-actin (tumor cell migration) outputs, and mediates lipolysis, thalamic and hippocampal synaptic modulation, neurite/neurogenesis control, and vasodilation [#14, #37, #15, #20, #17, #16, #19]. Receptor activity is shaped by IC3-loop and transmembrane residues required for G-protein coupling [#25, #27], by ligand-selectivity determinants in the N-terminal ectodomain [#28, #30], and by homologous desensitization via GRK2 phosphorylation\\u2014augmented by PKA, cross-inhibited by M3/PKC/RKIP, and dependent on caveolin-1 [#9, #10, #24]. VPAC2 traffics to the plasma membrane and to primary cilia via a C-terminal RDYR signal recognized by Tubby, the BBSome, and Arl6 [#13]. VIPR2 copy-number gain at 7q36.3 increases receptor transcription and cAMP signaling in patient lymphocytes and, in BAC transgenic mice acting through dopaminoceptive neurons, drives schizophrenia-related developmental, dopaminergic, and behavioral deficits [#31, #32].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing the gene's structure and ligand-selectivity architecture was the prerequisite for understanding how VPAC2 discriminates VIP from PACAP and where it sits in the genome.\",\n      \"evidence\": \"Genomic clone characterization mapping VIPR2 to 7q36.3, plus VPAC2/PAC1 and VPAC1/VPAC2 chimeric receptor binding/cAMP assays\",\n      \"pmids\": [\"10481065\", \"10556928\", \"10491203\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the active ligand-receptor complex\", \"Selectivity mapped by domain swaps without residue-level resolution in these studies\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defining the ligand and receptor residues that govern VPAC2 binding and activation answered how the receptor is selectively engaged and enabled selective pharmacological tools.\",\n      \"evidence\": \"Alanine scanning of VIP and IC3/transmembrane mutagenesis (R172, K179, N216, IC3 residues) with binding, cAMP, Ca2+, phosphorylation and internalization assays in heterologous cells\",\n      \"pmids\": [\"10801840\", \"11498510\", \"16650965\", \"15821106\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal/cryo-EM structure\", \"Coupling to non-Gs pathways at residue level incompletely mapped\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Knockout of Vipr2 answered whether the receptor is required for the circadian clock, establishing it as essential for sustained SCN rhythmicity and clock-gene expression.\",\n      \"evidence\": \"Vipr2-null mice with behavioral monitoring and SCN clock-gene in situ/Northern analysis\",\n      \"pmids\": [\"12086606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve single-cell versus circuit-level requirement\", \"Mechanism of intercellular coupling not defined here\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Electrophysiology in null and antagonist-treated slices answered whether VPAC2 mediates VIP's acute neuronal actions and the firing-rate rhythm, establishing a cellular basis for its clock role.\",\n      \"evidence\": \"SCN slice recording from Vipr2-/- and wild-type mice with selective VPAC2 agonist/antagonist\",\n      \"pmids\": [\"12542655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not link firing changes to molecular oscillator at single-cell level\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"These studies answered how VPAC2 controls clock function beyond rhythm maintenance \\u2014 gating photic input \\u2014 and how it shapes adaptive immunity by setting the Th2/Th1 balance via specific transcription factors.\",\n      \"evidence\": \"pERK/c-FOS immunohistochemistry under light pulses in Vipr2-/- SCN; transcription factor (c-Maf, JunB) analysis in CD4 T cells from transgenic/KO/WT mice\",\n      \"pmids\": [\"15071099\", \"15187104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors linking VPAC2-cAMP to ERK gating not defined\", \"Direct cis-regulatory targets of c-Maf/JunB at IL-4/IL-5 not mapped here\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Subtype-selective pharmacology and KO revealed VPAC2 uses divergent downstream pathways \\u2014 cAMP-independent PKC for neuroprotection and PKA for synaptic enhancement \\u2014 broadening the model beyond a single Gs-cAMP output.\",\n      \"evidence\": \"Vipr2-/- mice and selective agonists/antagonists with PKC/PKA inhibitors in excitotoxicity, hippocampal field recording, lipolysis and thalamic recording paradigms\",\n      \"pmids\": [\"15872042\", \"15935995\", \"15514088\", \"16641377\", \"15821106\", \"16709822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of cAMP-independent PKC coupling unresolved\", \"Splice-variant dominant-negative mechanism shown only in transfection\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Smooth-muscle studies answered how VPAC2 signaling is terminated and cross-regulated, defining GRK2-mediated homologous desensitization and its inhibition by M3/PKC/RKIP cross-talk.\",\n      \"evidence\": \"RKIP(S153A) and GRK2 mutant expression, co-IP, phosphorylation and internalization assays in smooth muscle cells\",\n      \"pmids\": [\"17170028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalizability beyond gastric smooth muscle untested\", \"In vivo relevance of cross-talk not demonstrated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"PKA was shown to amplify GRK2-mediated desensitization and single-cell imaging confirmed VPAC2 is required for synchronous oscillator coupling, refining the desensitization and circadian-coupling models.\",\n      \"evidence\": \"GRK2(S685A) mutagenesis with cAMP/desensitization assays; Per1-GFP live confocal imaging in Vipr2-/- and antagonist-treated SCN slices\",\n      \"pmids\": [\"18077607\", \"18554318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coupling mechanism (which signal synchronizes cells) not fully resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"These studies answered where VPAC2 is trafficked and how its surface behavior is modulated, defining ciliary targeting via an RDYR/BBSome pathway, caveolin-1-dependent internalization, and RAMP interactions.\",\n      \"evidence\": \"C-terminal/RDYR mutagenesis with Tubby/BBSome/Arl6 knockdown and ciliary imaging; caveolin-1 siRNA/KO and RAMP co-transfection with surface expression and G-protein assays\",\n      \"pmids\": [\"23862016\", \"23499767\", \"22946657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of ciliary versus plasma-membrane signaling not resolved\", \"RAMP modulation shown only in heterologous cells\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Patient lymphocyte and BAC transgenic studies answered whether VIPR2 copy-number gain is causally pathogenic, establishing increased VPAC2-cAMP signaling in dopaminoceptive neurons as the disease-relevant mechanism.\",\n      \"evidence\": \"cAMP/transcription assays in patient lymphocytes; conditional VIPR2 BAC transgenic mouse with Drd1a-Cre intersectional rescue and behavioral/dopaminergic readouts\",\n      \"pmids\": [\"21346763\", \"31444475\", \"25575489\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking elevated cAMP to D2 receptor abnormality unresolved\", \"Human causal evidence remains correlative at cellular level\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Intersectional genetics resolved VPAC2-expressing cells as an autonomous, functionally powerful pacemaker subset, and additional KO studies extended VPAC2's roles to neurite outgrowth and refractive (myopia) control.\",\n      \"evidence\": \"VPAC2-Cre cell-type-specific CK1\\u03b5/Bmal1 deletion with behavior and TTFL imaging; cortical neuron neurite assays with PKA dissection; Vipr2-KO with retinal scRNA-seq, ERG and refraction\",\n      \"pmids\": [\"32636383\", \"33234609\", \"32581681\", \"33318135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How VPAC2-cell intrinsic clock entrains the broader circuit not fully defined\", \"Bipolar-cell signaling pathway to refractive development unmapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Tumor cell studies answered how VPAC2 drives migration, defining a PI3K\\u03b3-PIP3-WAVE2-Rac-actin pathway distinct from canonical cAMP signaling.\",\n      \"evidence\": \"VIPR2 silencing/overexpression with PI3K activity, PIP3 imaging, WAVE2-ARP3-actin co-IP and migration assays in breast cancer cells\",\n      \"pmids\": [\"36237322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"G-protein link between VPAC2 and PI3K\\u03b3 not defined\", \"Single cell-line context, in vivo metastasis untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How VPAC2 selects among its divergent effector pathways (Gs-cAMP/PKA, PKC, PI3K\\u03b3) in a tissue- and ligand-specific manner, and the structural basis of biased signaling and ciliary versus surface function, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No active-state structure of VPAC2\", \"Determinants of pathway bias across tissues unknown\", \"Functional role of ciliary localization in vivo undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 20, 25]},\n      {\"term_id\": \"GO:0004930\", \"supporting_discovery_ids\": [25, 27, 28]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [13, 24, 37]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [20, 25, 9]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [0, 11, 34]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 5, 39]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 20, 21]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VIP\", \"PACAP\", \"GRK2\", \"RKIP\", \"CAV1\", \"RAMP1\", \"RAMP2\", \"RAMP3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}