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Showing ADCYAP1R1 — PAC1 is a alias.

ADCYAP1R1

Pituitary adenylate cyclase-activating polypeptide type I receptor · UniProt P41586

Length
468 aa
Mass
53.3 kDa
Annotated
2026-06-09
61 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ADCYAP1R1 (PAC1R) is a class B G protein-coupled receptor that recognizes the neuropeptide PACAP through a conserved extracellular-domain fold and transduces this signal into diverse neuronal, endocrine, and immune outcomes (PMID:21625560). Receptor function is diversified by alternative splicing: variants differ in ligand affinity and in coupling to Gs/cAMP versus Gq/inositol phosphate pathways, and structural work on the VIP-bound short and null variants shows that the spliced null loop engages ECL2 and the ECD N-terminal helix to set variant-selective VIP responsiveness (PMID:41264251, PMID:11278585). Isoform identity also determines biological output—'hop'-expressing neuroblasts couple to both cAMP and phosphoinositide signaling and are mitogenically stimulated, whereas 'short'-isoform cortical precursors raise only cAMP and are mitogenically inhibited (PMID:9753193). Downstream, PAC1R signals canonically via AC/cAMP/PKA and PKC/ERK: it enhances presynaptic vesicular acetylcholine release through an AC/cAMP/PKA/nitric oxide cascade (PMID:19958833), drives prolactin promoter activity and mRNA synthesis in pituitary cells with self-induction of the receptor (PMID:21539889), auto-regulates PACAP expression through parallel PKA, novel-PKC, and ERK activation (PMID:27745706), and promotes ILC2 proliferation and IL-5/IL-13 production via ERK (PMID:40713003). Non-canonically, PAC1R undergoes palmitoylation-dependent (Cys25) nuclear translocation triggered by allosteric modulators or by oxidative/blue-light stress, where it binds the promoters of its own and the PACAP gene to upregulate them and interacts with SP1 to drive a Huntingtin-NRSF neuropeptide program (PMID:35593471, PMID:33647387, PMID:36555637). Its transcription is controlled by estrogen receptor alpha acting at an ERE that contains the PTSD-risk SNP rs2267735, providing a hormonal link to fear-related expression (PMID:27959335). At the circuit level, PAC1R in locus coeruleus noradrenergic neurons is required for anxiety-related behavior within an anterior-insula→LC pathway (PMID:39396708).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1998 Medium

    Established that PAC1R splice-isoform identity, not ligand alone, dictates second-messenger coupling and opposing mitogenic outcomes, explaining context-dependent PACAP biology.

    Evidence RT-PCR isoform typing with cAMP/PI assays and proliferation assays in primary neuronal cultures

    PMID:9753193

    Open questions at the time
    • Molecular basis of isoform-specific coupling not structurally resolved
    • Single lab, primary culture only
  2. 1999 Low

    Linked PAC1R transcription to apoptosis/cell-cycle regulators by showing p53 and Zac induce the gene, but only at the expression-readout level.

    Evidence Reporter assays and p53/Zac overexpression in cell culture

    PMID:10366751

    Open questions at the time
    • No direct promoter-binding dissection
    • Single lab, expression readout only
  3. 2001 High

    Demonstrated that tissue-specific splicing (exon 3a in spermatogenic cells) reshapes PACAP affinity and Gs/Gq coupling, extending the splicing-diversification principle to the reproductive tract.

    Evidence Cloning of PAC1R(3a), stable HEK293 expression, radioligand binding, cAMP and IP assays, RT-PCR

    PMID:11278585

    Open questions at the time
    • Functional role in spermatogenesis not tested in vivo
    • Structural basis of altered coupling not determined
  4. 2005 Low

    Positioned PAC1R to inhibit prolactin secretion by localizing it to a subset of tuberoinfundibular dopamine neurons in the arcuate nucleus.

    Evidence RT-PCR, in situ hybridization, dual immunofluorescence for PAC1R and tyrosine hydroxylase in ewe hypothalamus

    PMID:15869565

    Open questions at the time
    • Functional consequence inferred, not directly tested
    • Restricted to one species and cell group
  5. 2009 High

    Defined a presynaptic AC/cAMP/PKA/NO mechanism by which PAC1R enhances cholinergic synaptic transmission, distinguishing it from postsynaptic and PLC routes.

    Evidence Whole-cell patch-clamp EPSC recordings with AC/PKA/PLC/NOS inhibitors and cAMP mimicry in ciliary ganglion neurons

    PMID:19958833

    Open questions at the time
    • NO source and downstream presynaptic targets not identified
    • Receptor isoform not specified
  6. 2011 High

    Resolved the conserved class B ECD fold of PAC1R and confirmed it as the PACAP-recognition module, unifying hormone binding across the family.

    Evidence 1.9 Å X-ray crystallography with alanine-scan peptide binding and cell-based cAMP/mutant assays

    PMID:21625560

    Open questions at the time
    • Full-length receptor and transmembrane activation not captured
    • Isoform-specific ECD differences not addressed
  7. 2011 Medium

    Showed PAC1R drives prolactin gene expression via Gs/cAMP and ERK/PKC and is itself upregulated by PACAP, introducing receptor auto-induction.

    Evidence PAC1R transfection, prolactin promoter-reporter, ERK Western blot, and mRNA assays in GH3 pituitary cells

    PMID:21539889

    Open questions at the time
    • Transcription factors mediating prolactin induction not identified
    • Single cell line
  8. 2016 Medium

    Established hormonal control of PAC1R transcription through ERα at an ERE overlapping the PTSD-risk SNP rs2267735, mechanistically connecting estrogen, the risk allele, and receptor expression.

    Evidence In vitro ERE binding, cell-culture E2 treatment, mouse fear conditioning, and human genotype-expression correlation

    PMID:27959335

    Open questions at the time
    • Causal link to PTSD behavior not demonstrated
    • Allele-specific binding effect size modest
  9. 2016 Medium

    Dissected two parallel PAC1R signaling branches—PKA and dimer-dependent Wnt/β-catenin—governing stem-cell viability and neural differentiation.

    Evidence Proliferation, migration, apoptosis, patch-clamp assays with PKA (H-89) and Wnt (XAV939) inhibition in human ADSCs

    PMID:26798992

    Open questions at the time
    • Mechanism of Wnt engagement by receptor dimers unresolved
    • Single lab, ex vivo cells
  10. 2016 Medium

    Defined the PAC1R-driven PACAP auto-regulatory circuit requiring parallel PKA, novel PKC, and ERK, and ruled out EGR1 as the mediator.

    Evidence Kinase inhibitors, RT-PCR, and EGR1 siRNA in NB-1 neuroblastoma cells with PAC1R agonist maxadilan

    PMID:27745706

    Open questions at the time
    • Transcription factor mediating PACAP induction unidentified
    • Single cell line
  11. 2019 Medium

    Identified doxycycline/minocycline as direct ECD-binding positive allosteric modulators of PAC1R, mapping key residues ASN60 and ASP116.

    Evidence Molecular docking, ITC binding, cAMP assay, and ECD site-directed mutagenesis

    PMID:31056648

    Open questions at the time
    • In vivo relevance of PAM activity untested
    • Effect on Gq coupling not examined
  12. 2019 Medium

    Showed the ADCYAP1R1 promoter has a hormetic, SP1-dependent response to H2O2, linking oxidative state to receptor transcription.

    Evidence Promoter cloning, reporter assay, SP1 inhibitor mithramycin A, and SP1-site deletion in SH-SY5Y cells

    PMID:31353704

    Open questions at the time
    • In vivo oxidative regulation not tested
    • Mechanism of biphasic switch unclear
  13. 2021 High

    Determined the first PAC1R ECD–antagonist co-structure and developed picomolar antagonist peptides with in vivo efficacy.

    Evidence X-ray co-crystallography of ECD-antagonist, SAR binding/inhibition, and rat maxadilan-induced blood-flow model

    PMID:33715378

    Open questions at the time
    • Antagonism in CNS circuits not assessed
    • Full-receptor binding mode not captured
  14. 2021 Medium

    Showed oxidative and blue-light stress trigger palmitoylation-dependent (Cys25) nuclear translocation of PAC1R coupled to its own promoter upregulation, extending the non-canonical nuclear mechanism to stress signaling.

    Evidence PAC1R-eGFP imaging, NAC/2-bromopalmitate inhibition, C25A mutagenesis, Western blot, reporter assay in CHO and RGC-5 cells

    PMID:33647387

    Open questions at the time
    • How a membrane GPCR reaches the nucleus mechanistically unresolved
    • Physiological trigger in vivo unclear
  15. 2022 Medium

    Established that allosterically induced nuclear PAC1R binds the PAC1R and PACAP promoters and recruits transcription factors, defining a receptor-as-transcriptional-regulator mode requiring Cys25 palmitoylation.

    Evidence Confocal imaging, ChIP-PCR, ChIP-seq, C25A mutagenesis, and promoter-reporter assays

    PMID:35593471

    Open questions at the time
    • Direct DNA binding vs. cofactor recruitment not separated
    • Functional importance relative to membrane signaling unknown
  16. 2022 Medium

    Connected the nuclear PAC1R fragment to a transcriptional program via SP1 interaction, Huntingtin upregulation, and NRSF derepression of neuropeptide genes.

    Evidence Nuclear translocation imaging, PAC1R-SP1 Co-IP, Western blot, and D-gal aging mouse model

    PMID:36555637

    Open questions at the time
    • Single Co-IP for the PAC1R-SP1 interaction without reciprocal validation
    • Origin of the 35 kDa nuclear fragment not defined
  17. 2022 Medium

    Defined a PAC1R/JNK/TPH1 axis by which a PACAP-family peptide protects astrocytes from oxidative stress.

    Evidence Primary astrocyte culture, qRT-PCR, immunofluorescence, lentiviral knockdown, viability and Western blot assays

    PMID:36037970

    Open questions at the time
    • Receptor-proximal coupling to JNK not mapped
    • In vivo relevance untested
  18. 2024 High

    Demonstrated that PAC1R in locus coeruleus noradrenergic neurons is required for anxiety behavior within a defined anterior-insula→LC PACAP circuit.

    Evidence In situ hybridization, conditional cell-type PAC1R deletion, retrograde tracing, chemogenetics, aIC PACAP shRNA, and behavioral tests

    PMID:39396708

    Open questions at the time
    • Downstream signaling in LC neurons not dissected
    • Sex-specific and hormonal modulation not addressed
  19. 2025 High

    Resolved the structural basis of splice-variant-selective VIP responsiveness, showing the null loop reshapes ECD/ECL2 engagement and Gs allostery.

    Evidence Cryo-EM of VIP-bound Gs-coupled PAC1sR and PAC1nR, MD simulations, and multi-endpoint pharmacology

    PMID:41264251

    Open questions at the time
    • PACAP-bound complexes of the variants not compared
    • Functional consequence in native neurons untested
  20. 2025 Low

    Indicated PAC1R signaling in the nucleus accumbens selectively blocks D1-mediated, not D2-mediated, cocaine reinstatement.

    Evidence PAC1R/PACAP expression mapping, retrograde tracing, and intra-NAcc pharmacological infusion in cocaine reinstatement assays (preprint)

    PMID:bio_10.1101_2025.03.17.643720

    Open questions at the time
    • Preprint, not peer reviewed
    • No molecular mechanism beyond receptor selectivity
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How membrane-resident PAC1R is processed and trafficked to the nucleus, and how this transcriptional mode is balanced against canonical Gs/Gq signaling in vivo, remains unresolved.
  • Mechanism of receptor entry into the nucleus unknown
  • Relative physiological weight of nuclear vs. membrane signaling unquantified
  • No in vivo validation of the nuclear transcriptional program

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0048018 receptor ligand activity 2 GO:0140110 transcription regulator activity 2 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 3 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-112316 Neuronal System 2
Partners
ADCYAP1ESR1SP1VIP

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 Crystal structure of the PAC1R extracellular domain (ECD) at 1.9 Å resolution reveals it adopts the same consensus fold as other Class B GPCRs. Binding studies and cell-based assays with alanine-scanned peptides and mutated receptor confirm that PAC1R uses this conserved ECD fold for PACAP binding, unifying the hormone-recognition mechanism for this receptor family. X-ray crystallography (1.9 Å), alanine-scan peptide binding assays, cell-based cAMP assays, mutant receptor functional assays PloS one High 21625560
2025 Cryo-EM structures of VIP-bound, Gs-coupled PAC1R short variant (PAC1sR) and null variant (PAC1nR) reveal that the alternatively spliced null loop in PAC1nR transiently engages residues in extracellular loop 2 (ECL2) and the N-terminal helix of the ECD, resulting in differential engagement of VIP with these domains and the top of TM2/ECL1. This structural difference underlies the selectively enhanced VIP (but not PACAP) functional activity across multiple signaling endpoints at PAC1sR compared to PAC1nR. MD simulations further predict differential Gs protein interactions with the two variants when VIP-bound, with greater allosteric influence of Gs on VIP affinity at PAC1sR. Cryo-EM structure determination, molecular dynamics (MD) simulations, pharmacological signaling assays across multiple functional endpoints Proceedings of the National Academy of Sciences of the United States of America High 41264251
1998 PAC1R isoform expression determines second-messenger coupling and mitogenic outcome: sympathetic neuroblasts expressing the 'hop' receptor isoform show PACAP-induced increases in both cAMP and PI (phosphoinositide) signaling and are mitogenically stimulated, whereas cerebral cortical precursors expressing primarily the 'short' isoform show only cAMP increases and are mitogenically inhibited. Thus, opposing mitogenic effects of PACAP correlate with differential receptor isoform expression and distinct intracellular signaling. RT-PCR isoform identification, cAMP and PI second-messenger assays, cell proliferation assays in primary neuronal cultures Journal of neuroscience research Medium 9753193
2001 A novel alternatively spliced exon (exon 3a, encoding 24 amino acids) inserted into the extracellular domain of PAC1R during spermatogenesis generates PAC1R(3a). In HEK293 cells stably expressing PAC1R(3a), ligand binding affinity for PACAP-38 is increased 6-fold and coupling to both cAMP (Gs) and inositol phosphate (Gq) signaling pathways is altered relative to wild-type PAC1R. PAC1R(3a) mRNA is preferentially expressed in seminiferous tubules, round spermatids, and Sertoli cells. Cloning and sequencing of novel splice variant, stable transfection of HEK293 cells, radioligand binding assays, cAMP and inositol phosphate signaling assays, RT-PCR expression analysis The Journal of biological chemistry High 11278585
2009 PACAP acts via selective high-affinity PAC1Rs to enhance nicotinic synaptic transmission at parasympathetic ciliary ganglion neurons by increasing spontaneous EPSC frequency and amplitude. The mechanism requires adenylate cyclase (AC)/cAMP/PKA signaling (not PLC), and acts presynaptically to increase vesicular ACh release (quantal content), not postsynaptic nAChR function. Nitric oxide (NO) signaling downstream of AC is critical: PACAP-induced increases in EPSC frequency, amplitude, and quantal content are mimicked by NO donor and abolished by NOS inhibition. Electrophysiology (whole-cell patch clamp, spontaneous and evoked EPSC recordings), pharmacological inhibitors of AC, PKA, PLC, NOS; 8-Bromo-cAMP mimicry; quantal content analysis Molecular and cellular neurosciences High 19958833
2016 Estradiol (E2) regulates ADCYAP1R1 expression through estrogen receptor alpha (ERα) binding to an estrogen response element (ERE) in the ADCYAP1R1 gene that contains the PTSD-risk SNP rs2267735. In vitro, E2/ERα binds less efficiently to the ERE containing the risk C allele. In vivo in mice, fear conditioning and E2 additively increase ADCYAP1R1 expression. In women with low serum E2, the CC genotype associates with lower ADCYAP1R1 expression. In vitro ERE binding assays (E2/ERα), cell culture E2 treatment with ADCYAP1R1 expression measurement, mouse fear conditioning with E2 treatment, human genotype-expression correlation Translational psychiatry Medium 27959335
1999 The tumor suppressor p53 and zinc finger protein Zac induce expression of the PAC1-R gene, establishing a transcriptional regulatory link between apoptosis/cell-cycle arrest pathways and PAC1-R expression. Gene reporter assays, overexpression of p53 and Zac in cell culture with PAC1-R gene expression readout Brain research. Molecular brain research Low 10366751
2011 PAC1R stimulates prolactin promoter activity and mRNA synthesis in pituitary GH3 cells through Gs/cAMP and ERK/PKC signaling pathways; transfection of PAC1R expression vector dramatically potentiates the prolactin promoter response to PACAP proportional to receptor amount, and PAC1R itself is induced by PACAP (auto-upregulation). Transfection of PAC1R expression vector into GH3 cells, prolactin promoter-reporter assay, ERK phosphorylation assay (Western blot), RT-PCR for prolactin and GH mRNA Molecular and cellular endocrinology Medium 21539889
2016 In human adipose-derived stem cells (hADSCs), PAC1R activation by the selective agonist maxadilan promotes cell proliferation, migration, and anti-apoptotic effects, and enhances neural differentiation. Two distinct PAC1R-coupled pathways are identified: ligand-dependent PKA signaling enhances viability and neural differentiation (blocked by H-89); and dimer-dependent Wnt/β-catenin signaling also promotes viability (blocked by XAV939). Cell Counting Kit-8 proliferation assay, cell cycle analysis, wound-healing migration assay, Annexin V apoptosis assay, mitochondrial membrane potential assay, Western blot, qPCR, whole-cell patch clamp, pharmacological inhibition of PKA and Wnt pathways Journal of cellular and molecular medicine Medium 26798992
2022 PAC1R undergoes nuclear translocation when treated with positive allosteric modulators PACAP(28-38) or TAT peptide. Nuclear PAC1R binds the promoter regions of PAC1R and PACAP genes (demonstrated by ChIP-PCR), upregulating their expression. Nuclear translocation requires palmitoylation at Cys25 (abolished by mutation C25A or palmitoylation inhibitor 2-bromopalmitate). ChIP-seq analysis identifies transcription factors SP1, Zic2, GATA1, REST, and YY1 as potentially recruited by nuclear PAC1R. Confocal fluorescence microscopy (nuclear translocation), ChIP-PCR (promoter binding), site-directed mutagenesis (C25A), palmitoylation inhibitor treatment, ChIP-sequencing, promoter-reporter assays Acta biochimica et biophysica Sinica Medium 35593471
2021 Blue light and hydrogen peroxide (H2O2) trigger nuclear translocation of PAC1R (observed in PAC1R-CHO cells expressing PAC1R-eGFP and in retinal ganglion cells RGC-5 with native PAC1R). Nuclear translocation is blocked by ROS scavenger NAC and palmitoylation inhibitor 2-bromopalmitate, and is markedly reduced by the C25A mutation in PAC1R. Nuclear translocation positively correlates with upregulation of PAC1R expression and promoter activity. Fluorescence microscopy (nuclear translocation of PAC1R-eGFP), pharmacological inhibition (NAC, 2-bromopalmitate), site-directed mutagenesis (C25A), Western blot, promoter-reporter assay Biochimica et biophysica acta. General subjects Medium 33647387
2022 PAC1R positive allosteric modulator SPAM1 triggers nuclear translocation of PAC1R. The nuclear 35 kDa (but not 15 kDa) fragment of PAC1R interacts with SP1 to upregulate Huntingtin (Htt) expression, which then attenuates NRSF (neuron-restrictive silencer factor) binding to NRSE, leading to upregulated expression of NRSF-target neuropeptides (PACAP, BDNF, TH, SYN1). Fluorescence microscopy (nuclear translocation), co-immunoprecipitation (nuclear PAC1R-SP1 interaction), Western blot, in vivo D-gal aging mouse model, cell viability assays International journal of molecular sciences Medium 36555637
2016 PACAP auto-regulates its own expression through PAC1R activation in human neuroblastoma NB-1 cells. PAC1R-mediated PACAP gene induction requires parallel, independent activation of PKA, novel (but not conventional) PKC isoforms, and ERK. EGR1 induction by PACAP requires PKC and ERK (not PKA), but siRNA knockdown of EGR1 did not affect PACAP auto-regulation, excluding EGR1 from the PACAP auto-regulatory pathway. Pharmacological kinase inhibitors (PKA, PKC, MEK), RT-PCR for PACAP mRNA, siRNA knockdown of EGR1, PAC1R-selective agonist Maxadilan Neuropeptides Medium 27745706
2019 The human ADCYAP1R1 gene promoter (cloned 2,526 bp region from -2500 to +26) shows a hormetic response to H2O2 in SH-SY5Y cells: low concentrations (<10 nM) activate the promoter in a dose-dependent manner via SP1 binding sites (blocked by mithramycin A and SP1 site deletion mutants), whereas higher concentrations (>10 nM) inhibit promoter activity. Promoter cloning, reporter assay, SP1 inhibitor (mithramycin A), deletion mutagenesis of SP1 binding sites Journal of food biochemistry Medium 31353704
2019 Doxycycline and minocycline function as positive allosteric modulators (PAMs) of PAC1-R by binding the N-terminal extracellular domain (PAC1-EC1). Isothermal titration calorimetry confirms direct binding. Site-directed mutagenesis identifies ASN60 as the most important residue for PAM binding, with ASP116 playing a sensitive marginal role. Tetracycline/tigecycline derivatives show lower affinity and lack PAM activity. Computational molecular docking, isothermal titration calorimetry, cAMP assay with PACAP27, site-directed mutagenesis of PAC1-EC1 Acta biochimica et biophysica Sinica Medium 31056648
2021 A co-crystal structure of a PAC1R antagonist peptide (des(24-42) Maxadilan analog 18) bound to the PAC1R extracellular domain was determined, representing the first structural data for a PAC1R antagonist. SAR studies identified peptide modifications that increased PAC1R inhibitory activity to the pM IC90 range. Analog 17 and 18 showed in vivo efficacy in a rat Maxadilan-induced blood flow pharmacodynamic model at 0.3 mg/kg subcutaneous dosing. X-ray co-crystallography of PAC1R ECD with antagonist peptide, in vitro PAC1R binding/inhibition assays, in vivo rat pharmacodynamic model Journal of medicinal chemistry High 33715378
2022 Peptide OM-LV20 protects astrocytes from oxidative stress via a PAC1R/JNK/TPH1 signaling axis: OM-LV20 increases TPH1 expression in astrocytes through PAC1R and the JNK signaling pathway, protecting against H2O2-induced decreases in cell viability and catalase levels. Primary astrocyte culture, quantitative RT-PCR, double immunofluorescence, lentiviral infection (loss-of-function), cell viability analysis, Western blotting The Journal of biological chemistry Medium 36037970
2003 PAC1-R is expressed in reactive astrocytes but not resting astrocytes. Immunostaining of transgenic mice (GFAP-EGFP) following cortical stab wound revealed PAC1-R immunoreactivity specifically in EGFP/GFAP-positive reactive astrocytes (and vimentin-positive cells) around the wound at 5 days post-surgery, but not in the contralateral hemisphere. Transgenic GFAP-EGFP mouse model, cortical stab wound surgery, immunohistochemistry for PAC1-R, GFAP, vimentin, CD11b, NeuN Brain research. Molecular brain research Medium 12824050
2008 PAC1-R heterozygous (-/+) mice fail to use geomagnetic orientation or fear signals to guide memory retrieval (no errors when maze is rotated 180° relative to geomagnetic field or upon fear signal exposure), whereas wild-type mice do make errors in these conditions. This implicates PAC1-R in gating passage of geomagnetic and fear sensory signals for memory retrieval. Behavioral testing in PAC1-R heterozygous transgenic mutant mice vs. wild-type littermates in multiple-maze memory tasks with rotation and fear signal challenges Journal of molecular neuroscience : MN Low 18781286
2024 PACAP/PAC1R signaling in the locus coeruleus (LC) from anterior insular cortex (aIC) PACAP neurons regulates anxiety-related behaviors. PAC1R mRNA is highly expressed in LC noradrenergic neurons. Targeted deletion of PAC1R from noradrenergic cells produces a hyperactive/low anxiety phenotype. Selective activation of PACAP neurons in the aIC increases anxiety. Retrograde tracing confirmed aIC PACAP neurons project to the LC. shRNA knockdown of PACAP in the aIC decreases anxiety. Histochemistry (PAC1R mRNA in situ hybridization), conditional cell-type-specific PAC1R deletion, retrograde neurocircuit tracing, chemogenetic activation of aIC PACAP neurons, shRNA knockdown of PACAP in aIC, open field and elevated-plus maze behavioral tests Neurochemistry international High 39396708
2025 In a rat nucleus accumbens core (NAcc) model, endogenous PAC1R (ADCYAP1R1) is expressed in NAcc and PACAP mRNA is present in medial prefrontal cortical projections to NAcc. Intra-NAcc PACAP infusion blocked cocaine-primed reinstatement and blocked reinstatement driven by D1 receptor agonist co-infusion, but did not block reinstatement driven by D2 receptor agonist, demonstrating PAC1R signaling in NAcc selectively interferes with D1-mediated (not D2-mediated) reinstatement mechanisms. In situ hybridization/immunofluorescence for PAC1R expression, retrograde tracing for mPFC→NAcc PACAP projections, intra-NAcc pharmacological infusion, cocaine-primed and receptor agonist-driven reinstatement behavioral assays bioRxivpreprint Low bio_10.1101_2025.03.17.643720
2023 Celastrol promotes cAMP production after spinal cord injury (SCI) by upregulating the VIP-ADCYAP1R1-GNAS signaling pathway, thereby inhibiting JNK phosphorylation and preventing apoptosis in injured spinal cord tissue. In vivo SCI mouse model, cAMP measurement, Western blot (JNK phosphorylation, apoptotic markers), gene expression analysis Biomedicine & pharmacotherapy Low 37531781
2025 PACAP/PAC1R signaling promotes ILC2 (group 2 innate lymphoid cell) proliferation and IL-5/IL-13 cytokine production via the ERK pathway. In OVA-induced allergic rhinitis mice, PAC1R knockdown or antagonist (PA-8) markedly suppressed ILC2 proliferation and cytokine production. ERK inhibitor PD98059 reversed PAC1R-mediated ILC2 activation, and PAC1R knockdown decreased p-ERK and ILC2 numbers. OVA-induced AR mouse model, PAC1R siRNA knockdown, PAC1R antagonist PA-8, ERK inhibitor PD98059, Western blot (p-ERK), flow cytometry (ILC2s, IL-5/IL-13) Archives of biochemistry and biophysics Medium 40713003
2005 PAC1R is expressed on tuberoinfundibular dopamine (TIDA) neurons in the arcuate nucleus of the ewe hypothalamus; dual immunofluorescence shows 21.2% of arcuate tyrosine hydroxylase-positive dopaminergic neurons co-express PAC1R, while other hypothalamic dopaminergic cell groups show little (<3%) co-localization. This positions PAC1R to mediate PACAP's inhibition of prolactin secretion via direct action on TIDA neurons. RT-PCR, in situ hybridization, immunohistochemistry, dual immunofluorescence for PAC1R and tyrosine hydroxylase Journal of neuroendocrinology Low 15869565

Source papers

Stage 0 corpus · 61 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 ADCYAP1R1 genotype associates with post-traumatic stress symptoms in highly traumatized African-American females. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 86 23505260
2013 ADCYAP1R1 and asthma in Puerto Rican children. American journal of respiratory and critical care medicine 85 23328528
1998 Opposing mitogenic regulation by PACAP in sympathetic and cerebral cortical precursors correlates with differential expression of PACAP receptor (PAC1-R) isoforms. Journal of neuroscience research 75 9753193
2016 Functional evaluation of a PTSD-associated genetic variant: estradiol regulation and ADCYAP1R1. Translational psychiatry 66 27959335
2011 Crystal structure of the PAC1R extracellular domain unifies a consensus fold for hormone recognition by class B G-protein coupled receptors. PloS one 57 21625560
2003 Expression of the receptor for pituitary adenylate cyclase-activating polypeptide (PAC1-R) in reactive astrocytes. Brain research. Molecular brain research 53 12824050
2013 PAC1 receptor (ADCYAP1R1) genotype is associated with PTSD's emotional numbing symptoms in Chinese earthquake survivors. Journal of affective disorders 49 23394710
2001 Novel alternatively spliced exon in the extracellular ligand-binding domain of the pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1R) selectively increases ligand affinity and alters signal transduction coupling during spermatogenesis. The Journal of biological chemistry 42 11278585
2000 Cellular distribution of the splice variants of the receptor for pituitary adenylate cyclase-activating polypeptide (PAC(1)-R) in the rat brain by in situ RT-PCR. Brain research. Molecular brain research 39 10648899
1998 The pituitary adenylate cyclase activating polypeptide type 1 receptor (PAC1-R) is expressed on gastric ECL cells: evidence by immunocytochemistry and RT-PCR. Annals of the New York Academy of Sciences 39 9928007
2020 Circulating PACAP peptide and PAC1R genotype as possible transdiagnostic biomarkers for anxiety disorders in women: a preliminary study. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 35 31910434
2017 Association of Posttraumatic Stress Disorder With rs2267735 in the ADCYAP1R1 Gene: A Meta-Analysis. Journal of traumatic stress 35 28746747
1999 Induction of the PAC1-R (PACAP-type I receptor) gene by p53 and Zac. Brain research. Molecular brain research 35 10366751
2007 Pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1R) co-localizes with activity-dependent neuroprotective protein (ADNP) in the mouse brains. Regulatory peptides 33 17942168
2022 Peptide OM-LV20 protects astrocytes against oxidative stress via the 'PAC1R/JNK/TPH1' axis. The Journal of biological chemistry 31 36037970
2008 Discovery and SAR of hydrazide antagonists of the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor type 1 (PAC1-R). Bioorganic & medicinal chemistry letters 27 18272364
2017 PACAP and PAC1R are differentially expressed in motor cortex of amyotrophic lateral sclerosis patients and support survival of iPSC-derived motor neurons. Journal of cellular physiology 25 28926110
2006 Pituitary adenylyl cyclase-activating polypeptide (PACAP) and its receptor (PAC1-R) are positioned to modulate afferent signaling in the cochlea. Neuroscience 25 16876955
2015 Gene-by-social-environment interaction (GxSE) between ADCYAP1R1 genotype and neighborhood crime predicts major depression symptoms in trauma-exposed women. Journal of affective disorders 24 26334183
2009 PACAP/PAC1R signaling modulates acetylcholine release at neuronal nicotinic synapses. Molecular and cellular neurosciences 23 19958833
2004 Duplicated receptors for VIP and PACAP (VPAC1R and PAC1R) in a teleost fish, Fugu rubripes. Journal of molecular endocrinology 22 15525598
2017 Screening of genetic variants in ADCYAP1R1, MME and 14q21 in a Swedish cluster headache cohort. The journal of headache and pain 20 28831700
2006 Pituitary adenylyl cyclase-activating polypeptide (PACAP) and its receptor (PAC1-R) in the cochlea: evidence for specific transcript expression of PAC1-R splice variants in rat microdissected cochlear subfractions. Neuroscience 18 16626868
2020 Impact of ADCYAP1R1 genotype on longitudinal fear conditioning in children: interaction with trauma and sex. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 17 32590837
2017 PAC1 receptor (ADCYAP1R1) genotype and problematic alcohol use in a sample of young women. Neuropsychiatric disease and treatment 15 28652748
2008 Expression and in vitro regulation of pituitary adenylate cyclase-activating polypeptide (pacap38) and its type I receptor (pac1-r) in the gonads of tilapia (Oreochromis mossambicus). Reproduction (Cambridge, England) 15 19106203
2016 PAC1R agonist maxadilan enhances hADSC viability and neural differentiation potential. Journal of cellular and molecular medicine 14 26798992
2007 Distribution and localization of pituitary adenylate cyclase-activating polypeptide-specific receptor (PAC1R) in the rostral migratory stream of the infant mouse brain. Regulatory peptides 14 17900711
2011 Stimulatory effect of pituitary adenylate-cyclase activating polypeptide (PACAP) and its PACAP type I receptor (PAC1R) on prolactin synthesis in rat pituitary somatolactotroph GH3 cells. Molecular and cellular endocrinology 13 21539889
2019 Expression Patterns of PACAP and PAC1R Genes and Anorexigenic Action of PACAP1 and PACAP2 in Zebrafish. Frontiers in endocrinology 12 31031705
2018 Estrogen-Dependent Upregulation of Adcyap1r1 Expression in Nucleus Accumbens Is Associated With Genetic Predisposition of Sex-Specific QTL for Alcohol Consumption on Rat Chromosome 4. Frontiers in genetics 12 30564267
2016 Interactions between Two Different G Protein-Coupled Receptors in Reproductive Hormone-Producing Cells: The Role of PACAP and Its Receptor PAC1R. International journal of molecular sciences 11 27681724
2022 Positive allosteric regulation of PAC1-R up-regulates PAC1-R and its specific ligand PACAP. Acta biochimica et biophysica Sinica 10 35593471
2010 Expression analysis of PAC1-R and PACAP genes in zebrafish embryos. Journal of molecular neuroscience : MN 10 20526695
2023 The discovery of the new mechanism: Celastrol improves spinal cord injury by increasing cAMP through VIP-ADCYAP1R1-GNAS pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 9 37531781
2021 The ADCYAP1R1 Gene Is Correlated With Posttraumatic Stress Disorder Symptoms Through Diverse Epistases in a Traumatized Chinese Population. Frontiers in psychiatry 9 34163384
1995 Assignments of the genes for rat pituitary adenylate cyclase activating polypeptide (Adcyap1) and its receptor subtypes (Adcyap1r1, Adcyap1r2, and Adcyap1r3). Cytogenetics and cell genetics 9 7656595
2019 Hormesis effect of hydrogen peroxide on the promoter activity of neuropeptide receptor PAC1-R. Journal of food biochemistry 8 31353704
2005 Expression of pituitary adenylate cyclase activating polypeptide type 1 receptor (PAC1R) in the ewe hypothalamus: distribution and colocalization with tyrosine hydroxylase-immunoreactive neurones. Journal of neuroendocrinology 8 15869565
2021 Discovery of Selective Pituitary Adenylate Cyclase 1 Receptor (PAC1R) Antagonist Peptides Potent in a Maxadilan/PACAP38-Induced Increase in Blood Flow Pharmacodynamic Model. Journal of medicinal chemistry 7 33715378
2019 The allosteric modulation effects of doxycycline, minocycline, and their derivatives on the neuropeptide receptor PAC1-R. Acta biochimica et biophysica Sinica 7 31056648
2016 PKA, novel PKC isoforms, and ERK is mediating PACAP auto-regulation via PAC1R in human neuroblastoma NB-1 cells. Neuropeptides 7 27745706
2021 Blue light induces the nuclear translocation of neuropeptide receptor PAC1-R associated with the up-regulation of PAC1-R its own in reactive oxygen species associated way. Biochimica et biophysica acta. General subjects 6 33647387
2023 Hypothalamic PACAP/PAC1R Involvement in Feeding and Body Weight Regulation. Endocrinology 5 36917637
2008 Performance of PAC1-R heterozygous mice in memory tasks-II. Journal of molecular neuroscience : MN 5 18781286
2006 PAC1-R null isoform expression in human prostate cancer tissue. The Prostate 5 16372333
2006 PACAP receptor (PAC1-R) expression in rat and rhesus monkey thymus. Annals of the New York Academy of Sciences 5 16888229
2022 Novel Small Molecule Positive Allosteric Modulator SPAM1 Triggers the Nuclear Translocation of PAC1-R to Exert Neuroprotective Effects through Neuron-Restrictive Silencer Factor. International journal of molecular sciences 4 36555637
2024 Integrated Transcriptomic and Proteomic Study of the Mechanism of Action of the Novel Small-Molecule Positive Allosteric Modulator 1 in Targeting PAC1-R for the Treatment of D-Gal-Induced Aging Mice. International journal of molecular sciences 3 38612681
2022 A novel small positive allosteric modulator of neuropeptide receptor PAC1-R exerts neuroprotective effects in MPTP mouse Parkinson's disease model. Acta biochimica et biophysica Sinica 3 36082935
2024 The pivotal role of PACAP/PAC1R signaling from the anterior insular cortex to the locus coeruleus on anxiety-related behaviors of mice. Neurochemistry international 2 39396708
2023 Does age matter in genetics? The role of ADCYAP1R1 in sex-specific risk for posttraumatic stress disorder in trauma-exposed preadolescent children. Journal of psychiatric research 2 37392718
2022 The main effect and gene-environment interaction effect of the ADCYAP1R1 polymorphism rs2267735 on the course of posttraumatic stress disorder symptoms-A longitudinal analysis. Frontiers in psychiatry 2 36386994
2018 PAC1R Genotype to Phenotype Correlations in Autism Spectrum Disorder. Autism research : official journal of the International Society for Autism Research 2 30556326
2007 Ontogeny of PAC1-R and VPAC1-R in the frog, Rana esculenta. Peptides 2 17524522
2001 Application and modification of in situ RT-PCR for detection and cellular localization of PAC1-R splice variant mRnas in frozen brain sections. Biotechnic & histochemistry : official publication of the Biological Stain Commission 2 11440308
2025 Structural basis of modified ligand selectivity from N-terminal PAC1R alternative splicing. Proceedings of the National Academy of Sciences of the United States of America 1 41264251
2023 Effect of PACAP/PAC1R on Follicle Development of Djungarian Hamster (Phodopus sungorus) with the Variation of Ambient Temperatures. Biology 1 36829590
2025 Molecular Basis of PAC1R Allosteric Modulation with Lipids in Membranes. bioRxiv : the preprint server for biology 0 39974954
2025 PACAP/PAC1R activation promotes group 2 innate lymphoid cells-dependent allergic rhinitis via ERK pathway. Archives of biochemistry and biophysics 0 40713003
2018 [New function of PACAP on hematopoiesis through PACAP specific receptor (PAC1R)]. Nihon yakurigaku zasshi. Folia pharmacologica Japonica 0 29887573

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