Affinage

ADORA1

Adenosine receptor A1 · UniProt P30542

Length
326 aa
Mass
36.5 kDa
Annotated
2026-04-28
29 papers in source corpus 15 papers cited in narrative 16 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ADORA1 encodes the adenosine A1 receptor, a Gi-coupled GPCR that inhibits adenylyl cyclase and suppresses cAMP accumulation upon adenosine binding, functioning broadly as a modulator of neuronal signaling, immune regulation, and cell survival across diverse tissues (PMID:1646713). In the brain, ADORA1 forms a signaling complex with neurabin and RGS4 that attenuates receptor output, and it heteromerizes with the A2A receptor to exert negative allosteric modulation of A2AR activity; the Parkinson's disease-linked G279S mutation selectively disrupts this heteromer interface without altering canonical Gi coupling (PMID:35674130, PMID:36279718, PMID:27134041). In cancer cells, ADORA1 engages PI3K/AKT signaling to promote proliferation, and its loss or inhibition upregulates PD-L1 through ATF3- or IRF1-dependent transcriptional programs, thereby modulating tumor immune evasion (PMID:33293832, PMID:32183950, PMID:40948543). ADORA1 protein stability is regulated by NEDD4-1-mediated ubiquitination at residue LYS265, and a homozygous G279S mutation in ADORA1 causes early-onset parkinsonism with cognitive dysfunction (PMID:41576610, PMID:27134041).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1991 High

    The fundamental molecular identity and signaling mechanism of ADORA1 were established: the cloned receptor binds adenosine with A1-type pharmacology and couples to Gi to inhibit cAMP, resolving its classification as the molecular correlate of the brain A1 adenosine receptor.

    Evidence Heterologous expression in CHO and Cos cells with cAMP assays and radioligand binding

    PMID:1646713

    Open questions at the time
    • Structural basis of Gi coupling not resolved
    • Endogenous tissue-level signaling dynamics not addressed
    • No downstream effector pathways mapped beyond cAMP
  2. 2016 Medium

    A human genetic link was drawn between ADORA1 and neurodegeneration: a homozygous G279S missense mutation segregated with early-onset parkinsonism and cognitive dysfunction, establishing ADORA1 as a Parkinson's disease gene, though the molecular mechanism of pathogenicity was unknown.

    Evidence Homozygosity mapping and exome sequencing in an affected family; transfected HEK293 cell studies

    PMID:27134041

    Open questions at the time
    • Mechanism by which G279S causes disease was not identified
    • Only one family studied
    • Interaction with dopamine D1 receptor was unchanged, leaving pathogenic interaction partner unresolved
  3. 2018 Medium

    A downstream effector pathway was mapped: ADORA1 activation was placed upstream of PKC and KATP channel (Kir6.2/SUR1) signaling in neurons, linking the receptor to hypoxia-induced injury mechanisms.

    Evidence Pharmacological agonist/antagonist and PKC inhibitor epistasis in PC12 cells under intermittent hypoxia

    PMID:29380238

    Open questions at the time
    • Pathway placement relies on pharmacological epistasis in a single cell line
    • Direct physical interaction between ADORA1 and PKC not shown
    • Relevance to in vivo neuronal injury not validated
  4. 2020 High

    Two oncogenic signaling outputs were defined: ADORA1 loss upregulates PD-L1 via transcription factor ATF3 to promote immune evasion, while ADORA1 overexpression drives proliferation through PI3K/AKT, revealing context-dependent pro- and anti-tumorigenic roles.

    Evidence CRISPR/shRNA with ATF3 epistasis in melanoma/NSCLC plus immune-competent mouse models; PI3K inhibitor epistasis with xenografts in HCC

    PMID:32183950 PMID:33293832

    Open questions at the time
    • How Gi-coupled signaling leads to PI3K/AKT activation was not resolved
    • ATF3-dependent PD-L1 mechanism was cancer-type specific and not universal
    • Direct receptor-proximal signaling steps connecting ADORA1 to ATF3 were not mapped
  5. 2021 Medium

    The PI3K/AKT pathway downstream of ADORA1 was extended to include GSK-3β/β-catenin in nasopharyngeal carcinoma, and a separate tumor-immune axis was identified whereby hypoxia-induced adenosine signals through ADORA1 on plasmacytoid dendritic cells to promote immunosuppression in hepatocellular carcinoma.

    Evidence TOP-Flash reporter and PI3K inhibitor epistasis in NPC cells; pDC depletion and ADORA1 antagonist in HCC mouse models

    PMID:33961854 PMID:34536555

    Open questions at the time
    • β-catenin activation pathway assumes linear cascade without ruling out parallel inputs
    • pDC recruitment mechanism through ADORA1 not molecularly defined
    • Generalizability across tumor types unclear
  6. 2022 High

    The PD-linked G279S mutation was mechanistically resolved: it specifically disrupts A1R-A2AR heteromerization at the TM5/6 interface, abolishing A1R's negative allosteric modulation of A2AR, while leaving canonical Gi signaling intact — providing a molecular explanation for the disease mechanism.

    Evidence NanoBiT complementation, BRET/FRET, radioligand binding, and molecular dynamics in HEK-293T cells with site-directed mutagenesis

    PMID:36279718

    Open questions at the time
    • Heteromer disruption not validated in neurons or patient tissue
    • Downstream consequence of lost allosteric modulation on dopaminergic circuits not shown
    • No rescue experiment to confirm heteromer loss is sufficient for disease phenotype
  7. 2022 Medium

    A neuronal signaling scaffold was defined: ADORA1 forms a tripartite complex with neurabin and RGS4 that constrains receptor signaling, and disrupting this complex enhances endogenous adenosine signaling enough to confer anticonvulsant and neuroprotective effects in vivo.

    Evidence Peptide disruption of A1R-neurabin interaction with ICV/intranasal delivery in kainate seizure and AD mouse models

    PMID:35674130

    Open questions at the time
    • Complex stoichiometry and assembly mechanism not reconstituted in vitro
    • Whether RGS4 acts as a direct GAP on ADORA1-coupled Gi in this complex not shown
    • Long-term safety and specificity of peptide disruption not addressed
  8. 2025 Medium

    The immune-evasion mechanism downstream of ADORA1 was shown to be context-dependent: in colon cancer, ADORA1 knockdown reduces PD-L1 through IRF1 rather than ATF3, establishing a parallel transcriptional axis for ADORA1-mediated PD-L1 regulation.

    Evidence shRNA knockdown with qPCR/Western blot for IRF1 and PD-L1 in CT26 cells, in vivo tumor models, T cell co-culture

    PMID:40948543

    Open questions at the time
    • Mechanism linking ADORA1 signaling to IRF1 transcription not identified
    • Whether ATF3 and IRF1 pathways are mutually exclusive or coexist in some tumors not tested
    • Upstream signal (cAMP vs. other) connecting ADORA1 to IRF1 unknown
  9. 2026 Medium

    A post-translational stability mechanism was uncovered: NEDD4-1 ubiquitinates ADORA1, and competitive inhibition of this ubiquitination at residue LYS265 stabilizes the receptor and suppresses osteoclast differentiation.

    Evidence Molecular docking, mass spectrometry, immunoprecipitation, and RANKL-induced osteoclast differentiation in vitro and OVX mouse model

    PMID:41576610

    Open questions at the time
    • Ubiquitination site mapping relies partly on molecular docking rather than mutagenesis alone
    • Whether NEDD4-1-mediated turnover regulates ADORA1 in neurons or other tissues is unknown
    • Downstream signaling changes from receptor stabilization not fully characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: the structural basis of ADORA1-A2AR heteromer assembly and its regulation in native neurons; the receptor-proximal signaling steps linking Gi inhibition of cAMP to PI3K/AKT activation and to transcription factor induction (ATF3/IRF1); and whether heteromer disruption is causally sufficient for parkinsonism in vivo.
  • No cryo-EM or crystal structure of A1R-A2AR heteromer
  • No in vivo genetic rescue of G279S heteromer phenotype
  • Receptor-proximal signaling branch point between cAMP-dependent and cAMP-independent outputs uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3
Partners
ADORA2AATF3IRF1NEDD4LPPP1R9ARGS4
Complex memberships
A1R-A2AR heteromerA1R/neurabin/RGS4 complex

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 RDC7 (ADORA1) encodes an A1 adenosine receptor that couples to Gi protein to decrease cAMP accumulation in forskolin-stimulated CHO cells; specific radioligand binding of [3H]CHA was demonstrated on membranes from transfected Cos cells, with pharmacological characteristics matching the natural brain A1 receptor. Stable transfection in CHO cells (cAMP assay), transient transfection in Cos cells (radioligand binding and displacement assays) The EMBO journal High 1646713
2020 Tumor ADORA1 deletion upregulates PD-L1 expression through transcriptional activator ATF3; ATF3 is identified as the factor that transcriptionally upregulates PD-L1 downstream of ADORA1 loss, thereby promoting immune evasion in melanoma and NSCLC. CRISPR/shRNA knockdown in cell lines, co-culture T cell assays, in vivo immune-competent mouse models, ATF3 deletion epistasis experiments Cancer cell High 32183950
2022 The Parkinson's disease-linked ADORA1 mutation G279S (G279^7.44S) does not alter A1R expression, ligand binding, constitutive activity, or G protein/β-arrestin coupling, but weakens A1R-A2AR heteromerization (NanoBiT assay), abolishing the heteromerization-dependent negative allosteric modulation that A1R normally exerts on A2AR constitutive activity and agonist-induced activation; molecular dynamics simulations indicate the mutation indirectly disrupts the TM5/6 heteromer interface. NanoBiT protein complementation assay, radioligand binding, BRET/FRET coupling assays in HEK-293T cells, molecular dynamics simulations, site-directed mutagenesis Biomedicine & pharmacotherapy High 36279718
2022 ADORA1 forms a complex with neurabin and RGS4 (A1R/neurabin/RGS4) in the brain; a peptide blocking the A1R-neurabin interaction enhances A1R signaling in response to endogenous adenosine, conferring anticonvulsant and neuroprotective effects in kainate seizure and Alzheimer's disease mouse models. Peptide disruption of protein-protein interaction, intracerebroventricular and intranasal peptide delivery, kainate seizure model, AD mouse model EEG recording JCI insight Medium 35674130
2018 ADORA1 activation by the agonist CCPA accelerates neuronal (PC12) cell injury after intermittent hypoxia via upregulation of PKC, Kir6.2 (KATP channel subunit), and SUR1; ADORA1 antagonism with DPCPX or PKC inhibition with CHE each alleviated injury and suppressed Kir6.2/SUR1 expression, placing ADORA1 upstream of the PKC/KATP pathway. Pharmacological agonist/antagonist treatment in PC12 cells under intermittent hypoxia, Western blot for pathway components, cell viability assays Molecular and cellular biochemistry Medium 29380238
2021 ADORA1 mediates pDC recruitment into tumors in hepatocellular carcinoma; hypoxia-induced extracellular adenosine generated downstream of HIF-1α-driven CD39/CD73 upregulation in HCC cells signals through ADORA1 to recruit plasmacytoid dendritic cells, which then suppress CD8+ T cell cytotoxicity and promote regulatory T cells. In vitro adenosine treatment with ADORA1 antagonist blockade, pDC depletion antibody, immune-competent HCC mouse model, mechanistic assessment of HIF-1α→CD39/CD73→eADO→ADORA1 axis Cancer letters Medium 34536555
2020 ADORA1 activates the PI3K/AKT oncogenic signaling pathway in hepatocellular carcinoma cells; PI3K inhibitor LY294002 blocks the proliferative and invasive effects of ADORA1 overexpression, and ADORA1 knockdown inhibits tumor growth and sensitizes cells to chemotherapy. ADORA1 overexpression and knockdown in HCC cells, Western blot for PI3K/AKT pathway, PI3K inhibitor epistasis, xenograft mouse model OncoTargets and therapy Medium 33293832
2021 ADORA1 activates the PI3K/AKT/GSK-3β/β-catenin signaling pathway in nasopharyngeal carcinoma cells; PI3K inhibitor LY294002 blocks ADORA1-mediated proliferation, invasion, and β-catenin transcriptional activity (TOP-Flash assay); ADORA1 silencing inhibits xenograft tumor growth in vivo. ADORA1 overexpression and knockdown, TOP-Flash luciferase reporter assay, Western blot, PI3K inhibitor epistasis, xenograft mouse model Life sciences Medium 33961854
2019 Adenosine induces EBV lytic reactivation through ADORA1 in EBV-associated gastric carcinoma; ADORA1 signaling is required to upregulate BZLF1 (encoding Zta), the key EBV lytic cycle regulator, linking ADORA1 to the EBV lytic cycle pathway. ADORA1 knockdown/pharmacological inhibition, BZLF1/Zta expression assays, EBVaGC xenograft mouse model International journal of molecular sciences Medium 30875759
2016 A homozygous missense mutation in ADORA1 (p.Gly279Ser) segregates with early-onset parkinsonism and cognitive dysfunction in a family; immunocytochemistry and Western blot in transfected HEK293 cells showed the mutation does not quantitatively alter interaction with dopamine receptor D1. Homozygosity mapping, exome sequencing, immunocytochemistry and Western blot in transfected HEK293 cells Movement disorders Medium 27134041
2014 Omega-3 PUFAs (DHA and EPA) induce apoptosis in gastric cancer cells via ADORA1 upregulation; blockade of ADORA1 with the selective antagonist DPCPX substantially reduces DHA/EPA-induced apoptosis, establishing ADORA1 as a required mediator of omega-3 PUFA-induced caspase-3 activation. Pharmacological antagonist (DPCPX) rescue, caspase-3 activity assay, apoptosis-related gene expression profiling in gastric cancer cells Frontiers in bioscience Low 24896321
2025 ADORA1 protects against sepsis-associated acute kidney injury by inhibiting pyroptosis via the noncanonical inflammasome pathway; ADORA1 agonist treatment downregulated cleaved caspase-11 and GSDMD expression, while ADORA1 antagonist produced opposite effects. LPS-induced sepsis mouse model, ADORA1 agonist/antagonist pharmacology, Western blot for pyroptosis markers (caspase-11, GSDMD), renal histology and function assays Tissue & cell Low 40090281
2025 ADORA1 forms a regulatory complex with PDE10A within the AKAP5 cAMP microdomain in IPAH pulmonary arterial smooth muscle cells; co-localization and protein-protein interaction studies showed this complex selectively exists under disease conditions, and dual inhibition of ADORA1 and PDE10A increases intracellular cAMP and induces anti-proliferative/pro-apoptotic effects in IPAH PASMCs and improves right ventricular function in PAH rat models. Protein-protein interaction studies, co-localization imaging in hPASMCs, siRNA silencing, dual pharmacological inhibition, MCT and SuHx rat PAH models bioRxiv (preprint)preprint Low
2026 Typhaneoside directly binds ADORA1 at residue LYS265 and competitively inhibits NEDD4-1-mediated ubiquitination of ADORA1, thereby stabilizing the receptor and suppressing osteoclast-specific gene expression (TRAP, CTSK, NFATc1) and RANKL-induced osteoclast differentiation. Molecular docking, mass spectrometry, immunoprecipitation, Western blot, TRAP staining, RANKL-induced osteoclast differentiation model, OVX mouse model Phytomedicine Medium 41576610
2025 In colon cancer, Adora1 knockdown reduces PD-L1 expression not through ATF3 but through reduced Irf1 expression, establishing an Adora1→Irf1→PD-L1 signaling axis that promotes immune evasion. Lentiviral shRNA knockdown of Adora1 in CT26 cells, Western blot/qPCR for Irf1 and PD-L1, in vivo tumor implantation, T cell co-culture exhaustion assays American journal of cancer research Medium 40948543
2025 ADORA1 inhibition in glioma induces apoptosis by augmenting kininogen-1 (KNG1) expression; ADORA1 inhibition also enhances T cell recruitment and increases sensitivity to anti-PD1 therapy in vivo. ADORA1 inhibition (pharmacological/genetic) in glioma cell lines and mouse models, KNG1 expression analysis, immune cell infiltration analysis, anti-PD1 combination in vivo Frontiers in oncology Low 40376586

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1991 The orphan receptor cDNA RDC7 encodes an A1 adenosine receptor. The EMBO journal 195 1646713
2020 ADORA1 Inhibition Promotes Tumor Immune Evasion by Regulating the ATF3-PD-L1 Axis. Cancer cell 164 32183950
2010 Association of the anxiogenic and alerting effects of caffeine with ADORA2A and ADORA1 polymorphisms and habitual level of caffeine consumption. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 140 20520601
2021 Plasmacytoid dendritic cells recruited by HIF-1α/eADO/ADORA1 signaling induce immunosuppression in hepatocellular carcinoma. Cancer letters 74 34536555
2016 Mutation in ADORA1 identified as likely cause of early-onset parkinsonism and cognitive dysfunction. Movement disorders : official journal of the Movement Disorder Society 31 27134041
2017 Metformin suppresses CRC growth by inducing apoptosis via ADORA1. Frontiers in bioscience (Landmark edition) 27 27814614
2020 ADORA1 Promotes Hepatocellular Carcinoma Progression via PI3K/AKT Pathway. OncoTargets and therapy 21 33293832
2019 Edaravone presents antidepressant-like activity in corticosterone model of depression in mice with possible role of Fkbp5, Comt, Adora1 and Slc6a15 genes. Toxicology and applied pharmacology 21 31344373
2020 ADORA2A variation and adenosine A1 receptor availability in the human brain with a focus on anxiety-related brain regions: modulation by ADORA1 variation. Translational psychiatry 19 33235193
2014 Omega-3 PUFAs induce apoptosis of gastric cancer cells via ADORA1. Frontiers in bioscience (Landmark edition) 19 24896321
2021 ADORA1 promotes nasopharyngeal carcinoma cell progression through regulation of PI3K/AKT/GSK-3β/β-catenin signaling. Life sciences 18 33961854
2016 Omega-3 Polyunsaturated Fatty Acids Enhance Cisplatin Efficacy in Gastric Cancer Cells by Inducing Apoptosis via ADORA1. Anti-cancer agents in medicinal chemistry 18 27025656
2009 Association analysis of adenosine A1 receptor gene (ADORA1) polymorphisms with schizophrenia in a Japanese population. Psychiatric genetics 17 19820430
2016 Differential Expression of Adenosine P1 Receptor ADORA1 and ADORA2A Associated with Glioma Development and Tumor-Associated Epilepsy. Neurochemical research 16 27038930
2019 Adenosine Induces EBV Lytic Reactivation through ADORA1 in EBV-Associated Gastric Carcinoma. International journal of molecular sciences 14 30875759
2021 ADORA1 is a diagnostic-related biomarker and correlated with immune infiltrates in papillary thyroid carcinoma. Journal of Cancer 13 34093805
2018 Activating adenosine A1 receptor accelerates PC12 cell injury via ADORA1/PKC/KATP pathway after intermittent hypoxia exposure. Molecular and cellular biochemistry 13 29380238
2022 The ADORA1 mutation linked to early-onset Parkinson's disease alters adenosine A1-A2A receptor heteromer formation and function. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 10 36279718
2021 Poria cum Radix Pini Rescues Barium Chloride-Induced Arrhythmia by Regulating the cGMP-PKG Signalling Pathway Involving ADORA1 in Zebrafish. Frontiers in pharmacology 9 34393777
2018 Withdrawal of caffeine after its chronic administration modifies the antidepressant-like activity of atypical antidepressants in mice. Changes in cortical expression of Comt, Slc6a15 and Adora1 genes. Psychopharmacology 8 29882086
2017 Upregulation of SERT and ADORA1 in broilers with acute right ventricular failure. Research in veterinary science 4 29174607
2022 A peptide blocking the ADORA1-neurabin interaction is anticonvulsant and inhibits epilepsy in an Alzheimer's model. JCI insight 3 35674133
2025 Activation ADORA1 protects against sepsis-associated acute kidney injury by inhibiting pyroptosis. Tissue & cell 1 40090281
2025 Breviscapine regulates lipid metabolism of microglia via the ADORA1/PPARα/ACOX1 pathway to promote spinal cord injury recovery. International immunopharmacology 1 40628044
2024 Introduction of a single-nucleotide variant, rs16851030, into the ADORA1 gene increased cellular susceptibility to hypoxia. Personalized medicine 1 39440484
2026 Typhaneoside suppresses osteoclastogenesis and osteoporosis by stabilizing ADORA1. Phytomedicine : international journal of phytotherapy and phytopharmacology 0 41576610
2025 Inhibiting ADORA1 enhances glioma apoptosis and increases its sensitivity to anti-PD1 therapy. Frontiers in oncology 0 40376586
2025 Precision Targeting in Gastric Cancer: AI-Driven Discovery of MET, ADORA2A, CDK5R1, and ADORA1. Assay and drug development technologies 0 40932634
2025 Adora1 promotes colon cancer immune evasion via Irf1-PD-L1 signal axis. American journal of cancer research 0 40948543