Affinage

ADCYAP1

Pituitary adenylate cyclase-activating polypeptide · UniProt P18509

Length
176 aa
Mass
18.8 kDa
Annotated
2026-06-09
22 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ADCYAP1 encodes the neuropeptide PACAP, a pleiotropic signaling molecule that acts through its G-protein coupled receptor PAC1R to coordinate central behavioral programs, peripheral neuronal survival and regeneration, and metabolic energy storage (PMID:32651949, PMID:37880634). In the brainstem, ADCYAP1+ neurons of the nucleus of the solitary tract and area postrema are both necessary and sufficient for the sickness behavior response to LPS, with chemogenetic activation recapitulating anorexia, adipsia, lethargy and temperature changes and inhibition diminishing them (PMID:36071158). In the forebrain, PACAP supports serotonergic tone and 5-HT1A-mediated prefrontal inhibitory control of motor activity, such that its loss produces hyperlocomotion, prepulse inhibition deficits and abnormal jumping behavior (PMID:16687500, PMID:16888223), and PACAP signaling lies downstream of Gα13 in an mPFC cAMP/PKA/NMDAR pathway whose disruption impairs social behavior and is rescued by PACAP-38 (PMID:40843621). In the periphery, PACAP is the most strongly upregulated gene in skin during peripheral nerve regeneration and dose-dependently enhances sensory axon outgrowth via PAC1R, and within dorsal root ganglia it acts as an intrinsic protective factor that suppresses neuropathic pain and facilitates axonal regeneration (PMID:32651949, PMID:37880634). PACAP also promotes adipogenesis, energy storage and insulin secretion in vivo and protects islet beta cells from cytokine-induced apoptosis (PMID:18446003, PMID:20007581). ADCYAP1 expression is silenced by promoter hypermethylation in cervical cancer (PMID:21109983).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2006 Medium

    Established that PACAP shapes central motor and sensorimotor gating behavior by supporting serotonergic tone, identifying 5-HT1A as a downstream effector of PACAP-dependent prefrontal inhibitory control.

    Evidence Adcyap1 knockout mice with prepulse inhibition assays, amphetamine/5-HT1A/SSRI pharmacology, neurochemical 5-HIAA measurement and c-Fos immunohistochemistry

    PMID:16687500 PMID:16888223

    Open questions at the time
    • Did not identify the specific neurons or circuits where PACAP acts on serotonergic signaling
    • Receptor (PAC1R vs other) mediating the behavioral effect not defined in vivo
  2. 2008 Medium

    Defined a peripheral metabolic role for PACAP, showing it promotes white adipose tissue accumulation, adipocyte differentiation and insulin secretion in vivo.

    Evidence Adcyap1 knockout mice analyzed by glucose/insulin tolerance tests, fat mass and adipocyte marker measurement, plasma hormone/adipokine assays

    PMID:18446003

    Open questions at the time
    • Tissue site of PACAP action (central vs adipose vs islet) not resolved
    • Receptor and intracellular pathway mediating adipogenesis not established
  3. 2009 Medium

    Placed ADCYAP1 downstream of DcR3 as a beta-cell survival mediator, providing a cell-autonomous anti-apoptotic function.

    Evidence Plasmid overexpression of Adcyap1 in NIT-1 insulinoma cells with cytokine-induced apoptosis assay; DNA microarray identification in DcR3-transgenic islets

    PMID:20007581

    Open questions at the time
    • Anti-apoptotic mechanism downstream of PACAP not dissected
    • Not validated in primary islets or in vivo
  4. 2011 Medium

    Identified an epigenetic mechanism silencing ADCYAP1, showing promoter hypermethylation represses its expression in cervical cancer.

    Evidence CpG methylation analysis in cancer cell lines and tissues with pharmacological demethylation/HDAC inhibitor reactivation

    PMID:21109983

    Open questions at the time
    • Functional consequence of ADCYAP1 loss for tumorigenesis not tested
    • Whether silencing is driver or passenger not established
  5. 2020 Medium

    Demonstrated that PACAP drives peripheral sensory axon outgrowth via PAC1R, linking it to nerve regeneration.

    Evidence Serial skin biopsy transcriptomics around carpal tunnel surgery plus PACAP treatment of human iPSC-derived sensory neurons with neurite length measurement

    PMID:32651949

    Open questions at the time
    • In vivo causal requirement of PACAP for human regeneration not tested
    • Intracellular signaling driving outgrowth not characterized
  6. 2022 High

    Resolved the circuit basis of sickness behavior, showing brainstem ADCYAP1+ NTS-AP neurons are necessary and sufficient for the behavioral response to LPS.

    Evidence Chemogenetic gain/loss-of-function in TRAP2 mice, single-nucleus RNA-seq cell typing and whole-brain FOS mapping

    PMID:36071158

    Open questions at the time
    • Whether the PACAP peptide itself (vs other markers of these neurons) mediates the behavior not isolated
    • Downstream target neurons of the ADCYAP1+ population not fully defined
  7. 2023 Medium

    Established PACAP as an intrinsic DRG protective factor coupling neuropathic pain suppression to axonal regeneration through PAC1R.

    Evidence Rat spared nerve crush model with intrathecal PACAP38, Adcyap1 siRNA knockdown and PAC1R antagonist, scRNA-seq, behavioral pain and regeneration readouts

    PMID:37880634

    Open questions at the time
    • Signaling cascade downstream of PAC1R in DRG not dissected
    • Single species/lab
  8. 2025 Medium

    Positioned ADCYAP1/PACAP within an mPFC Gα13/cAMP/PKA/NMDAR pathway controlling social behavior, with pharmacological rescue restoring synaptic and behavioral deficits.

    Evidence CRISPR Gα13 overexpression in mPFC pyramidal neurons, RNA-seq, PACAP-38 rescue, fiber photometry, Golgi staining, patch clamp and three-chamber socialization test

    PMID:40843621

    Open questions at the time
    • Direct molecular link from Gα13 to Adcyap1 transcription not defined
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether PACAP/glutamate co-transmission from the Kölliker-Fuse nucleus causally drives rapid autonomic compensation to hypotension remains unresolved.
  • No direct functional manipulation of the PACAP pathway
  • Causal contribution to blood pressure compensation untested

Mechanism profile

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

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2022 ADCYAP1+ neurons in the nucleus of the solitary tract and area postrema (NTS-AP) are both necessary and sufficient for sickness behavior responses to LPS (anorexia, adipsia, lethargy, temperature changes): activation of these neurons fully recapitulates LPS-induced sickness, while inhibition significantly diminishes all behavioral responses. Chemogenetic activation/inhibition of ADCYAP1+ neurons in TRAP2 mice combined with single-nucleus RNA sequencing to identify LPS-activated neural populations; whole-brain activity mapping (FOS expression) Nature High 36071158
2006 Loss of Adcyap1 (PACAP) in mice causes hyperlocomotion and prepulse inhibition deficits; the paradoxical antihyperkinetic effect of amphetamine in Adcyap1−/− mice depends on serotonin 1A (5-HT1A) receptor signaling, and amphetamine increases c-Fos-positive neurons in the prefrontal cortex of these mice, suggesting PACAP normally modulates 5-HT1A-mediated inhibitory prefrontal control of motor activity. Genetic knockout (Adcyap1−/− mice), prepulse inhibition assay, pharmacological manipulation (amphetamine, 5-HT1A agonist 8-OH-DPAT, fluoxetine), c-Fos immunohistochemistry The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 16687500
2006 Adcyap1−/− mice exhibit intense jumping behavior that is suppressed by the SSRI fluoxetine and the serotonin precursor 5-hydroxytryptophan, and these mice show reduced brain 5-HIAA, indicating that PACAP supports serotonergic tone that limits abnormal motor behavior. Genetic knockout (Adcyap1−/− mice), pharmacological treatment (fluoxetine, 5-HTP), neurochemical measurement of 5-HIAA Annals of the New York Academy of Sciences Medium 16888223
2008 Adcyap1−/− mice have markedly reduced white adipose tissue mass, hypoinsulinemia, and increased insulin sensitivity accompanied by decreased adipocyte differentiation marker aP2 and reduced plasma resistin, indicating that PACAP promotes energy storage, adipogenesis, and insulin secretion in vivo. Genetic knockout (Adcyap1−/− mice), glucose and insulin tolerance tests, fat mass measurement, adipocyte marker mRNA expression (aP2), plasma hormone and adipokine measurements, high-fat diet challenge Journal of pharmacological sciences Medium 18446003
2009 Forced overexpression of Adcyap1 in insulinoma NIT-1 cells protected them from cytokine-triggered apoptosis, establishing ADCYAP1 as a downstream mediator of DcR3-mediated islet beta cell survival. Plasmid-mediated overexpression of Adcyap1 in NIT-1 insulinoma cells, cytokine-induced apoptosis assay; DNA microarray identified Adcyap1 upregulation (>700-fold) in DcR3-transgenic islets Journal of immunology (Baltimore, Md. : 1950) Medium 20007581
2020 ADCYAP1 (PACAP) is the most strongly upregulated gene in skin during peripheral nerve regeneration after carpal tunnel release; PACAP signals through its G-protein coupled receptor (PAC1R) expressed on human iPSC-derived sensory neurons and dose-dependently enhances axon outgrowth in vitro. Transcriptional profiling of serial skin biopsies (pre/post carpal tunnel surgery), human iPSC-derived sensory neuron culture with PACAP treatment, neurite length measurement in vitro Brain : a journal of neurology Medium 32651949
2023 Adcyap1/PACAP38 is an intrinsic protective factor in dorsal root ganglion neurons linking neuropathic pain suppression and axonal regeneration: intrathecal PACAP38 mitigates mechanical hyperalgesia and facilitates axon regeneration, while Adcyap1 siRNA knockdown or PAC1R antagonist (PACAP6-38) both worsen pain and delay regeneration in a rat spared nerve crush model. scRNA-seq of rat DRGs, intrathecal PACAP38 administration, siRNA knockdown of Adcyap1, PAC1R antagonist (PACAP6-38) treatment; behavioral pain testing (mechanical hyperalgesia), axonal regeneration assessment BMC biology Medium 37880634
2011 The ADCYAP1 promoter is hypermethylated in cervical cancer cells and CIN lesions, silencing ADCYAP1 expression; this silencing is reversed by treatment with a DNA methyltransferase inhibitor (5-aza-2'-deoxycytidine) and/or histone deacetylase inhibitor (trichostatin A), establishing promoter hypermethylation as a mechanism of ADCYAP1 transcriptional repression in cervical cancer. Methylation analysis of CpG islands in ADCYAP1 promoter in cancer cell lines and tissue samples; pharmacological demethylation/HDAC inhibitor treatment followed by gene expression measurement Oncology reports Medium 21109983
2025 Gα13 overexpression in medial prefrontal cortex pyramidal neurons downregulates Adcyap1, reducing cAMP/PKA signaling and impairing NMDA receptor function; pharmacological activation with PACAP-38 rescues social deficits and restores synaptic function in Gα13-OE mice, placing ADCYAP1/PACAP downstream of Gα13 in a mPFC cAMP/PKA/NMDAR pathway controlling social behavior. CRISPR/Cas9-mediated Gα13 overexpression in mPFC pyramidal neurons; RNA-seq identifying Adcyap1 downregulation; pharmacological rescue with PACAP-38; fiber photometry; Golgi staining; whole-cell patch clamp; three-chamber socialization test Schizophrenia bulletin Medium 40843621
2025 A Kölliker-Fuse nucleus subpopulation co-expressing Adcyap1 (PACAP) and VGluT1 (Slc17a7) forms calyceal terminals around PKCδ+/GluD1+ extended amygdala neurons and becomes Fos-positive rapidly after acute hypotension, preceding vasopressin-mediated endocrine responses, suggesting PACAP/glutamate co-transmission mediates rapid autonomic compensation to falling blood pressure. Fos immunohistochemistry at 60 and 120 min after hydralazine-induced hypotension in rats; confocal immunohistochemistry of PACAP+ terminals around EA neurons; RNAscope in situ hybridization for Adcyap1/Slc17a7 co-expression in KF bioRxivpreprint Low bio_10.1101_2025.10.16.682741

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 Brainstem ADCYAP1+ neurons control multiple aspects of sickness behaviour. Nature 117 36071158
2006 Psychostimulant-induced attenuation of hyperactivity and prepulse inhibition deficits in Adcyap1-deficient mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 78 16687500
2020 Molecular and cellular correlates of human nerve regeneration: ADCYAP1/PACAP enhance nerve outgrowth. Brain : a journal of neurology 52 32651949
2008 Markedly reduced white adipose tissue and increased insulin sensitivity in adcyap1-deficient mice. Journal of pharmacological sciences 49 18446003
2017 Human Papillomavirus Genotypes and Methylation of CADM1, PAX1, MAL and ADCYAP1 Genes in Epithelial Ovarian Cancer Patients. Asian Pacific journal of cancer prevention : APJCP 28 28240513
2011 The role of ADCYAP1, adenylate cyclase activating polypeptide 1, as a methylation biomarker for the early detection of cervical cancer. Oncology reports 28 21109983
2006 Serotonergic inhibition of intense jumping behavior in mice lacking PACAP (Adcyap1-/-). Annals of the New York Academy of Sciences 20 16888223
2009 DcR3 protects islet beta cells from apoptosis through modulating Adcyap1 and Bank1 expression. Journal of immunology (Baltimore, Md. : 1950) 15 20007581
2018 Examination of Clock and Adcyap1 gene variation in a neotropical migratory passerine. PloS one 12 29324772
2023 Unveiling adcyap1 as a protective factor linking pain and nerve regeneration through single-cell RNA sequencing of rat dorsal root ganglion neurons. BMC biology 11 37880634
2016 Adcyap1 polymorphism covaries with breeding latitude in a Nearctic migratory songbird, the Wilson's warbler (Cardellina pusilla). Ecology and evolution 11 27252831
2015 Interactions between a Candidate Gene for Migration (ADCYAP1), Morphology and Sex Predict Spring Arrival in Blackcap Populations. PloS one 10 26684459
2010 Replication study of association between ADCYAP1 gene polymorphisms and schizophrenia. Psychiatric genetics 10 20414143
2002 Genetic variation screening and association studies of the adenylate cyclase activating polypeptide 1 (ADCYAP1) gene in patients with type 2 diabetes. Human mutation 9 11968092
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
2022 Shorebirds' Longer Migratory Distances Are Associated With Larger ADCYAP1 Microsatellites and Greater Morphological Complexity of Hippocampal Astrocytes. Frontiers in psychology 8 35185684
2008 Regulation of pituitary adenylyl cyclase-activating polypeptide (PACAP, ADCYAP1: adenylyl cyclase-activating polypeptide 1) in the treatment of schizophrenia. Expert opinion on therapeutic targets 8 18694377
2006 The neuropeptide genes TAC1, TAC3, TAC4, VIP and PACAP(ADCYAP1), and susceptibility to multiple sclerosis. Journal of neuroimmunology 8 17175032
2008 Association analysis of the pituitary adenylate cyclase-activating polypeptide (PACAP/ADCYAP1) gene in bipolar disorder. Psychiatric genetics 4 18349695
2023 Birds of a feather flock together: a dataset for Clock and Adcyap1 genes from migration genetics studies. Scientific data 2 37945571
2019 Epigenetic Profiles Reveal That ADCYAP1 Serves as Key Molecule in Gestational Diabetes Mellitus. Computational and mathematical methods in medicine 1 31485258
2025 Gα13 Overexpression in the Medial Prefrontal Cortex Disrupts Social Behavior Through the Adcyap1/cAMP/PKA/NMDAR Pathway. Schizophrenia bulletin 0 40843621

Missed literature

Know a paper Affinage missed for ADCYAP1? Flag it for the maintainers and the community.

No submissions yet.