{"gene":"ADRA1D","run_date":"2026-06-09T22:02:42","timeline":{"discoveries":[{"year":2016,"finding":"ADRA1D undergoes endogenous N-terminal (NT) domain cleavage at Leu90/Val91 in cultured human cells, producing a Δ1-91 isoform. This cleavage is not required for formation of scribble-syntrophin macromolecular complexes, but the Δ1-91 isoform shows greater agonist-stimulated functional responses than wild-type ADRA1D. Mutagenesis of the cleavage site abolished NT processing and reduced agonist responses below wild-type levels.","method":"SNAP near-infrared imaging, tandem-affinity purification MS/MS, co-immunoprecipitation, serial truncation mutagenesis, label-free dynamic mass redistribution signaling assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (TAP-MS, Co-IP, mutagenesis, functional signaling assay) in a single rigorous study establishing both the cleavage site and functional consequence","pmids":["27382054"],"is_preprint":false},{"year":2015,"finding":"ADRA1D forms an obligate modular homodimer at the plasma membrane that binds the PDZ scaffold proteins syntrophin (SNTA, SNTB1, SNTB2) and scribble (SCRIB) through its C-terminal PDZ ligand. Syntrophins and SCRIB compete for the PDZ ligand and can simultaneously co-exist within the ADRA1D multimer. Syntrophins ensure receptor plasma membrane localization and G-protein coupling, while SCRIB and syntrophins impart divergent pharmacological properties. No other GPCRs among 23 tested with Type I PDZ ligands interacted with syntrophins.","method":"Tandem affinity purification/mass spectrometry (TAP/MS), co-immunoprecipitation, dynamic mass redistribution functional assays, biochemical fractionation","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal Co-IP, proteomic TAP/MS, functional pharmacological assay, and negative control (23 other GPCRs), all in one study with multiple orthogonal methods","pmids":["26617989"],"is_preprint":false},{"year":2021,"finding":"ADRA1D protein was quantified to have the shortest degradation half-life (t1/2 = 0.52 h) among all nine adrenergic receptor subtypes tested, and degradation occurs primarily through the proteasome (reversed by bortezomib treatment).","method":"SNAP-epitope tag/near-infrared imaging cycloheximide-chase degradation assay, proteasome inhibitor (bortezomib) treatment, 96-well plate format","journal":"SLAS discovery : advancing life sciences R & D","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative CHX-chase assay with proteasome inhibitor validation in a single lab, two complementary formats (PAGE and 96-well)","pmids":["33402011"],"is_preprint":false},{"year":2024,"finding":"PRDM16, a transcription factor expressed in vascular smooth muscle cells (VSMCs), directly regulates the transcription of Adra1d. VSMC-specific Prdm16 knockout mice show significantly lower blood pressure during the active period and reduced mesenteric artery contraction in response to phenylephrine (an α1-adrenergic agonist), resulting in aberrant blood pressure circadian variation. PRDM16 also regulates clock genes (particularly Npas2) that control BP circadian variation.","method":"VSMC-specific conditional knockout mice, telemetric blood pressure measurement, ex vivo mesenteric artery myography with phenylephrine, transcriptional target identification","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO with functional vascular phenotype, blood pressure telemetry, and ex vivo functional assay, establishing ADRA1D as a direct transcriptional target of PRDM16","pmids":["39625782"],"is_preprint":false},{"year":2010,"finding":"Adra1d expression in C2 skeletal myoblasts is upregulated under survival conditions (IGF-I rescue of high-dose TNF-α-induced death) and downregulated under apoptotic conditions. siRNA knockdown of Adra1d resulted in significantly higher cell death across all incubation conditions, establishing that Adra1d expression is essential for skeletal myoblast survival.","method":"Insulin signaling array, qRT-PCR, siRNA gene silencing, cell viability assays under defined TNF-α/IGF-I conditions","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with quantified phenotypic readout under multiple conditions, single lab","pmids":["20110686"],"is_preprint":false},{"year":2020,"finding":"Patulin (PAT) exposure in HEK293 cells decreased ADRA1D mRNA and protein expression and altered downstream AMPK pathway signaling (ERK1/2, PI3K/Akt). Molecular docking indicated direct interaction of PAT with ADRA1A (and PRKAG3). NAC (antioxidant) ameliorated PAT-induced suppression of α1-AR, while BSO (GSH inhibitor) potentiated it, linking oxidative stress to ADRA1D downregulation.","method":"qPCR, western blotting, molecular docking, pharmacological modulation (Epi, metformin, BSO, NAC)","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, no mutagenesis or rescue experiment; molecular docking is computational; mechanistic pathway placement partially inferred","pmids":["33208818"],"is_preprint":false},{"year":2025,"finding":"In Alzheimer's disease mouse models (3xTg-AD), ADRA1 expression and epinephrine (EPI) levels are elevated. Neuronal ADRA1D knockdown (via intracerebroventricular AAV) suppressed STING/NF-κB/NLRP3 pathway activation, ameliorated tau hyperphosphorylation, and improved cognitive function. ADRA1D overexpression in wild-type mice induced tauopathy and neuroinflammation. Mechanistically, ADRA1D interacts with CXCR4 to form heterodimers, triggering cytoplasmic Ca2+ overload and STING/NF-κB/NLRP3 pathway activation.","method":"AAV-mediated neuronal ADRA1D knockdown and overexpression, co-immunoprecipitation, calcium flux assays, pharmacological antagonists, Western blot, behavioral testing","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo AAV KD/OE with defined molecular pathway, Co-IP for CXCR4 heterodimer, Ca2+ flux assays; single lab, multiple orthogonal methods","pmids":["40676669"],"is_preprint":false},{"year":2025,"finding":"In 3xTg-AD mice, gastrodin inhibits the ADRA1/NF-κB/NLRP3 pathway, reducing tau phosphorylation and neuroinflammation. Lentiviral overexpression of ADRA1 in vitro reversed gastrodin's suppression of NF-κB/NLRP3 activation and inflammatory cytokine release (IL-1β, IL-18). Aβ42-induced upregulation of ADRA1/NF-κB/NLRP3 was inhibited by gastrodin in SH-SY5Y cells.","method":"Lentiviral ADRA1 overexpression, Western blot, immunohistochemistry, ELISA, in vitro Aβ42 cell model","journal":"Phytotherapy research : PTR","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mechanistic placement relies on overexpression rescue without direct receptor mutagenesis or direct binding assay","pmids":["39963073"],"is_preprint":false},{"year":2025,"finding":"Lonicerin reduces high glucose-induced upregulation of ADRA1D in human aortic endothelial cells (HAECs), leading to decreased cytoplasmic Ca2+ levels, inhibition of calcineurin activity, NFAT1 phosphorylation, and prevention of endothelial-to-mesenchymal transition (EndMT). EC-specific overexpression of ADRA1D negated the inhibitory effects of lonicerin on EndMT and its therapeutic impact on diabetic vascular injury, establishing ADRA1D as a proximal mediator of the Ca2+/Calcineurin/NFAT1-dependent EndMT pathway.","method":"RNAi, plasmid overexpression, Western blot, qRT-PCR, immunofluorescence, flow cytometry, calcineurin activity assay, RNA sequencing, STZ-induced diabetic mouse model","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression rescue in both in vitro and in vivo (EC-specific), with Ca2+ flux and calcineurin activity measured; single lab, multiple orthogonal methods","pmids":["40398181"],"is_preprint":false},{"year":2023,"finding":"In a bleomycin mouse lung fibrosis model, noradrenaline from local adrenergic nerves (not adrenal sources) drives emergence of an αSMA+ fibroblast population expressing ADRA1D. Therapeutic delivery of the α1 adrenoreceptor antagonist terazosin reversed fibroblast accumulation and suppressed extracellular mitochondrial DNA (mtDNA) accumulation. In cultured normal human lung fibroblasts, costimulation with TGFβ1 and NA induced ADRA1D expression, ACTA2 upregulation, and extracellular mtDNA release, all opposed by terazosin.","method":"Surgical adrenergic nerve ablation vs. adrenal resection in bleomycin model, pharmacological antagonism (terazosin), cultured human lung fibroblasts with TGFβ1/NA stimulation, αSMA/ADRA1D immunostaining","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — nerve ablation and pharmacological experiments in vivo plus in vitro fibroblast model, multiple readouts; single lab","pmids":["36648147"],"is_preprint":false},{"year":2021,"finding":"In an in vitro OGD (oxygen-glucose deprivation) model of vascular dementia using PC12 cells, ADRA1D overexpression decreased apoptosis and lowered intracellular Ca2+ levels, while ADRA1D knockdown increased apoptosis and elevated Ca2+. Mechanistically, ADRA1D overexpression reduced PLCβ and IP3R expression, suggesting ADRA1D modulates Ca2+ homeostasis via the PLCβ/IP3R pathway.","method":"OGD PC12 cell model, lentiviral overexpression and siRNA knockdown of ADRA1D, TUNEL assay, RT-qPCR, Western blot, Fluo-3 AM Ca2+ imaging","journal":"Actas espanolas de psiquiatria","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, in vitro only, pathway inference from downstream expression changes without direct binding or kinetic assays","pmids":["38622006"],"is_preprint":false},{"year":2025,"finding":"In chromogranin A (CgA) knockout/PS19 tauopathy mice, cortical epinephrine (EPI) levels and Adra1 expression (elevated in PS19 mice relative to WT) were reduced back to near-normal. Treatment of WT hippocampal organotypic slice cultures with EPI or an Adra1 agonist promoted tau hyperphosphorylation and neurofibrillary tangle formation, while an Adra1 antagonist inhibited these effects, establishing a functional EPI-Adra1 signaling axis in tau pathogenesis.","method":"Transgenic mouse models (CgA-KO/PS19), transcriptomic and metabolite analysis, hippocampal organotypic slice culture pharmacology (EPI, Adra1 agonist, Adra1 antagonist), immunohistochemistry","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological gain- and loss-of-function in ex vivo slice culture with functional tau readout, plus in vivo genetic model; single lab, multiple methods","pmids":["40393970"],"is_preprint":false},{"year":2025,"finding":"Osthol (OST) downregulates ADRA1D expression in obese mice, suppressing Th17 differentiation (reduced CD4+IL-17A+ and CD4+RORγt+ cells). ADRA1D overexpression in vitro and in vivo partially reversed OST-mediated suppression of Th17 polarization, expression of lipogenic genes (FASN, PPARγ), and lipid droplet accumulation, establishing ADRA1D as a mediator of Th17 differentiation linked to obesity-associated immunometabolic dysregulation.","method":"HFD mouse model, in vitro Th17 differentiation (primary murine CD4+ T cells), ADRA1D overexpression (cells and mice), flow cytometry, ELISA, RT-qPCR, Western blot","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression rescue establishes ADRA1D dependence but mechanism of ADRA1D action on Th17 differentiation is not directly resolved; single lab","pmids":["41120583"],"is_preprint":false},{"year":2019,"finding":"ADRA1D mRNA and protein are downregulated in the injured spinal cord following brachial plexus root avulsion. The lncRNA MRAK034299, which targets Adra1d, is also downregulated post-avulsion, suggesting a lncRNA-mediated epigenetic mechanism contributes to reduced ADRA1D expression in motoneuron injury context.","method":"Microarray lncRNA/mRNA profiling, qRT-PCR validation, Western blot, immunofluorescence, in vivo rat brachial plexus avulsion model","journal":"Neurochemistry international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-expression of lncRNA and mRNA changes validated but causal mechanism not directly tested; single lab","pmids":["31783066"],"is_preprint":false},{"year":2017,"finding":"L-DOPA sensitizes vascular ADRA1 (alpha-1 adrenergic receptor) signaling in vascular smooth muscle cells (VSMCs) via the L-DOPA receptor GPR143. Specific knockout of Gpr143 in VSMCs attenuated phenylephrine-induced blood pressure elevation. L-DOPA enhanced phenylephrine-induced vasoconstriction and intracellular Ca2+ responses in vitro. Phenylephrine-augmented ERK phosphorylation was present in WT but not Gpr143-/y VSMCs.","method":"Gpr143 whole-body and VSMC-specific knockout mice, intravenous phenylephrine infusion with telemetric blood pressure, in vitro VSMC Ca2+ imaging, ERK phosphorylation assay","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO with defined vascular functional phenotype and in vitro mechanistic validation; single lab, multiple orthogonal methods","pmids":["28931752"],"is_preprint":false},{"year":2023,"finding":"L-DOPA receptor GPR143 physically interacts with ADRA1B at the second transmembrane (TM2) domain interface. A synthetic TAT-TM2 peptide disrupted the GPR143-ADRA1B interaction (co-immunoprecipitation) and suppressed GPR143-augmented phenylephrine-induced ERK phosphorylation in HEK293T cells co-expressing ADRA1B and GPR143.","method":"Chimeric receptor analysis (TM domain swapping), co-immunoprecipitation, TAT-peptide disruption, ERK phosphorylation assay in HEK293T cells","journal":"Biological & pharmaceutical bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chimeric analysis and Co-IP establish TM2 as the interaction interface with functional validation via peptide disruption; single lab, multiple methods. Note: this paper concerns ADRA1B primarily, with functional relevance to the ADRA1 subfamily including ADRA1D signaling context.","pmids":["37394637"],"is_preprint":false}],"current_model":"ADRA1D is a G protein-coupled α1-adrenergic receptor that localizes to the plasma membrane as an obligate modular homodimer scaffolded by PDZ proteins syntrophin and scribble; it undergoes endogenous N-terminal cleavage at Leu90/Val91 to generate a Δ1-91 isoform with enhanced agonist-stimulated signaling, is a direct transcriptional target of PRDM16 in vascular smooth muscle cells controlling blood pressure circadian rhythm, couples to Ca2+/calcineurin/NFAT1 and STING/NF-κB/NLRP3 inflammatory pathways in endothelial and neuronal cells, is sensitized by L-DOPA/GPR143 signaling to amplify vasoconstriction, and is essential for skeletal myoblast survival, with the shortest proteasome-dependent degradation half-life among all adrenergic receptor subtypes."},"narrative":{"mechanistic_narrative":"ADRA1D is a plasma-membrane G protein-coupled α1-adrenergic receptor that organizes into an obligate modular homodimer scaffolded through its C-terminal Type I PDZ ligand by the PDZ proteins syntrophin (SNTA, SNTB1, SNTB2) and scribble (SCRIB), which compete for the ligand yet can coexist within the multimer; syntrophins drive plasma-membrane localization and G-protein coupling while SCRIB and syntrophins impart divergent pharmacology [PMID:26617989]. The receptor undergoes endogenous N-terminal cleavage at Leu90/Val91 to generate a Δ1-91 isoform with enhanced agonist-stimulated signaling, and abolishing this processing reduces responsiveness below wild-type [PMID:27382054]. ADRA1D is among the most short-lived adrenergic receptors, turning over rapidly via the proteasome [PMID:33402011]. In vascular smooth muscle, Adra1d is a direct transcriptional target of PRDM16, and loss of this regulation lowers blood pressure during the active period and blunts phenylephrine-induced arterial contraction, linking the receptor to circadian blood-pressure control [PMID:39625782]; its vasoconstrictor signaling is further sensitized by L-DOPA acting through GPR143 to amplify phenylephrine-induced Ca2+ and ERK responses [PMID:28931752]. Across endothelial, neuronal, and immune contexts, ADRA1D acts as a proximal driver of intracellular Ca2+-dependent signaling — engaging the Ca2+/calcineurin/NFAT1 axis to promote endothelial-to-mesenchymal transition [PMID:40398181] and, via heterodimerization with CXCR4, triggering Ca2+ overload and STING/NF-κB/NLRP3 activation that promotes tau hyperphosphorylation and neuroinflammation [PMID:40676669]. ADRA1D expression is also required for skeletal myoblast survival [PMID:20110686].","teleology":[{"year":2010,"claim":"Established that ADRA1D expression has a cell-survival function beyond classical vasoactive signaling, in skeletal muscle.","evidence":"siRNA knockdown with viability readout under TNF-α/IGF-I conditions in C2 myoblasts","pmids":["20110686"],"confidence":"Medium","gaps":["Downstream survival pathway not defined","No receptor-domain or signaling mechanism linked to the phenotype"]},{"year":2015,"claim":"Defined the structural and scaffolding architecture of the receptor, answering how ADRA1D reaches the membrane and couples to G proteins.","evidence":"TAP/MS, reciprocal Co-IP, DMR functional assays with 23-GPCR negative control","pmids":["26617989"],"confidence":"High","gaps":["No structural model of the homodimer or PDZ interface","Functional consequence of SCRIB vs syntrophin competition not fully resolved"]},{"year":2016,"claim":"Identified an endogenous N-terminal cleavage event that generates a signaling-enhanced receptor isoform, revealing post-translational tuning of agonist responsiveness.","evidence":"NIR imaging, TAP-MS/MS, serial truncation and cleavage-site mutagenesis, DMR signaling assays in human cells","pmids":["27382054"],"confidence":"High","gaps":["Protease responsible for Leu90/Val91 cleavage unidentified","Physiological regulation of cleavage in vivo unknown"]},{"year":2017,"claim":"Showed that ADRA1 vasoconstrictor signaling is sensitized by L-DOPA through GPR143, connecting receptor function to blood-pressure regulation.","evidence":"Gpr143 whole-body and VSMC-specific KO mice, telemetric BP, VSMC Ca2+ imaging, ERK phosphorylation","pmids":["28931752"],"confidence":"Medium","gaps":["Direct ADRA1D-GPR143 interaction not demonstrated (subtype specificity within ADRA1 unresolved)","Mechanism of sensitization at the receptor level undefined"]},{"year":2021,"claim":"Quantified ADRA1D turnover, establishing it as the shortest-lived adrenergic receptor and proteasome-dependent for degradation.","evidence":"SNAP/NIR cycloheximide-chase degradation assay with bortezomib in 96-well and PAGE formats","pmids":["33402011"],"confidence":"Medium","gaps":["E3 ligase and degradation signal not identified","Single-lab measurement in heterologous cells"]},{"year":2023,"claim":"Mapped the TM2 interface used by GPR143 to augment ADRA1-subfamily signaling, providing a molecular handle for the sensitization mechanism.","evidence":"Chimeric TM-domain swapping, Co-IP, TAT-TM2 peptide disruption, ERK assays (study centered on ADRA1B)","pmids":["37394637"],"confidence":"Medium","gaps":["Direct relevance to ADRA1D vs ADRA1B not established","No structural validation of the interface"]},{"year":2024,"claim":"Identified ADRA1D as a direct transcriptional target of PRDM16 in VSMCs controlling circadian blood-pressure variation.","evidence":"VSMC-specific Prdm16 KO mice, BP telemetry, ex vivo mesenteric artery myography with phenylephrine","pmids":["39625782"],"confidence":"High","gaps":["Direct PRDM16 occupancy at the Adra1d locus not detailed here","Relative contribution of Adra1d vs clock-gene regulation to phenotype unresolved"]},{"year":2025,"claim":"Placed ADRA1D as a proximal Ca2+-driven effector across endothelial and neuronal pathology, signaling through calcineurin/NFAT1 (EndMT) and CXCR4-heterodimer/STING/NF-κB/NLRP3 (tauopathy/neuroinflammation).","evidence":"EC- and neuron-specific overexpression/knockdown in vivo and in vitro, Co-IP for CXCR4 heterodimer, Ca2+ flux and calcineurin assays, behavioral and tau readouts","pmids":["40398181","40676669","40393970"],"confidence":"Medium","gaps":["Whether the same receptor pool drives both calcineurin/NFAT1 and STING/NLRP3 outputs is unclear","ADRA1D-CXCR4 heterodimer requires reciprocal structural validation"]},{"year":null,"claim":"How the receptor's structural features (cleavage, dimerization, PDZ scaffolding, rapid turnover) mechanistically dictate which downstream Ca2+ pathway is engaged in a given tissue remains unknown.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking receptor processing/scaffolding to pathway selection","Protease and E3 ligase identities unknown","Subtype-specific roles vs ADRA1A/ADRA1B not delineated in shared pathways"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6]}],"complexes":[],"partners":["SNTA1","SNTB1","SNTB2","SCRIB","GPR143","CXCR4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P25100","full_name":"Alpha-1D adrenergic receptor","aliases":["Alpha-1A adrenergic receptor","Alpha-1D adrenoreceptor","Alpha-1D adrenoceptor","Alpha-adrenergic receptor 1a"],"length_aa":572,"mass_kda":60.5,"function":"Alpha-1 adrenergic receptors are G protein-coupled receptors for catecholamines that signal through the G(q) family of G proteins, including G(q) and G(11). Upon activation, they stimulate the phosphatidylinositol-calcium second messenger pathway, leading to calcium release from intracellular stores and activation of protein kinase C (PubMed:7746284). ADRA1D binds the catecholamine ligands norepinephrine and epinephrine (PubMed:7815325, PubMed:8024574, PubMed:8183249)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P25100/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADRA1D","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADRA1D","total_profiled":1310},"omim":[{"mim_id":"190196","title":"TRANSGLUTAMINASE 2; TGM2","url":"https://www.omim.org/entry/190196"},{"mim_id":"104221","title":"ALPHA-1A-ADRENERGIC RECEPTOR; ADRA1A","url":"https://www.omim.org/entry/104221"},{"mim_id":"104219","title":"ALPHA-1D-ADRENERGIC RECEPTOR; ADRA1D","url":"https://www.omim.org/entry/104219"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":6.6},{"tissue":"brain","ntpm":6.1},{"tissue":"cervix","ntpm":5.8}],"url":"https://www.proteinatlas.org/search/ADRA1D"},"hgnc":{"alias_symbol":["ADRA1R","ADRA1A","ADRA1"],"prev_symbol":[]},"alphafold":{"accession":"P25100","domains":[{"cath_id":"1.20.1070.10","chopping":"91-297_333-425","consensus_level":"medium","plddt":86.0404,"start":91,"end":425}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P25100","model_url":"https://alphafold.ebi.ac.uk/files/AF-P25100-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P25100-F1-predicted_aligned_error_v6.png","plddt_mean":64.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADRA1D","jax_strain_url":"https://www.jax.org/strain/search?query=ADRA1D"},"sequence":{"accession":"P25100","fasta_url":"https://rest.uniprot.org/uniprotkb/P25100.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P25100/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P25100"}},"corpus_meta":[{"pmid":"26577018","id":"PMC_26577018","title":"Sodium butyrate attenuates social behavior deficits and modifies the transcription of inhibitory/excitatory genes in the frontal cortex of an autism model.","date":"2015","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26577018","citation_count":199,"is_preprint":false},{"pmid":"29180230","id":"PMC_29180230","title":"Glucocorticoids, genes and brain function.","date":"2017","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/29180230","citation_count":107,"is_preprint":false},{"pmid":"1889803","id":"PMC_1889803","title":"Localization of the panhypopituitary dwarf mutation (df) on mouse chromosome 11 in an intersubspecific backcross.","date":"1991","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/1889803","citation_count":70,"is_preprint":false},{"pmid":"8325647","id":"PMC_8325647","title":"A physical map of 15 loci on human chromosome 5q23-q33 by two-color fluorescence in situ hybridization.","date":"1993","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8325647","citation_count":70,"is_preprint":false},{"pmid":"1676978","id":"PMC_1676978","title":"Genomic organization of adrenergic and serotonin receptors in the mouse: linkage mapping of sequence-related genes provides a method for examining mammalian chromosome evolution.","date":"1991","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/1676978","citation_count":67,"is_preprint":false},{"pmid":"26945602","id":"PMC_26945602","title":"Surgery accelerates the development of endometriosis in mice.","date":"2016","source":"American journal of obstetrics and gynecology","url":"https://pubmed.ncbi.nlm.nih.gov/26945602","citation_count":57,"is_preprint":false},{"pmid":"24310984","id":"PMC_24310984","title":"Methylomics analysis identifies epigenetically silenced genes and implies an activation of β-catenin signaling in cervical cancer.","date":"2013","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24310984","citation_count":57,"is_preprint":false},{"pmid":"27664956","id":"PMC_27664956","title":"Chronic stress accelerates the development of endometriosis in mouse through adrenergic receptor β2.","date":"2016","source":"Human reproduction (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/27664956","citation_count":55,"is_preprint":false},{"pmid":"22688145","id":"PMC_22688145","title":"Clinical response and side effects of metoclopramide: associations with clinical, demographic, and pharmacogenetic parameters.","date":"2012","source":"Journal of clinical gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/22688145","citation_count":52,"is_preprint":false},{"pmid":"26912402","id":"PMC_26912402","title":"Evolutionary Genetics of Hypoxia Tolerance in Cetaceans during Diving.","date":"2016","source":"Genome biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/26912402","citation_count":51,"is_preprint":false},{"pmid":"22661280","id":"PMC_22661280","title":"Genome-wide genetic associations with IFNγ response to smallpox vaccine.","date":"2012","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22661280","citation_count":46,"is_preprint":false},{"pmid":"21063774","id":"PMC_21063774","title":"Domperidone treatment for gastroparesis: demographic and pharmacogenetic characterization of clinical efficacy and side-effects.","date":"2010","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/21063774","citation_count":45,"is_preprint":false},{"pmid":"26991744","id":"PMC_26991744","title":"l-glutamine Improves Skeletal Muscle Cell Differentiation and Prevents Myotube Atrophy After Cytokine (TNF-α) Stress Via Reduced p38 MAPK Signal Transduction.","date":"2016","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/26991744","citation_count":43,"is_preprint":false},{"pmid":"29944106","id":"PMC_29944106","title":"Silver Nanoparticle Exposure Induces Neurotoxicity in the Rat Hippocampus Without Increasing the Blood-Brain Barrier Permeability.","date":"2018","source":"Journal of biomedical nanotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/29944106","citation_count":40,"is_preprint":false},{"pmid":"29138825","id":"PMC_29138825","title":"Utility of miR‑133a‑3p as a diagnostic indicator for hepatocellular carcinoma: An investigation combined with GEO, TCGA, meta‑analysis and bioinformatics.","date":"2017","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/29138825","citation_count":30,"is_preprint":false},{"pmid":"26381449","id":"PMC_26381449","title":"The association of DNA methylation and brain volume in healthy individuals and schizophrenia patients.","date":"2015","source":"Schizophrenia research","url":"https://pubmed.ncbi.nlm.nih.gov/26381449","citation_count":28,"is_preprint":false},{"pmid":"24465776","id":"PMC_24465776","title":"Genome wide expression analysis suggests perturbation of vascular homeostasis during high altitude pulmonary edema.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24465776","citation_count":28,"is_preprint":false},{"pmid":"12442007","id":"PMC_12442007","title":"Molecular analysis of adrenergic receptor genes and interleukin-4/interleukin-4 receptor genes in patients with interstitial cystitis.","date":"2002","source":"The Journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/12442007","citation_count":25,"is_preprint":false},{"pmid":"27382054","id":"PMC_27382054","title":"Endogenous N-terminal Domain Cleavage Modulates α1D-Adrenergic Receptor Pharmacodynamics.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27382054","citation_count":22,"is_preprint":false},{"pmid":"29870805","id":"PMC_29870805","title":"Mineralocorticoid receptor antagonism reverses diabetes-related coronary vasodilator dysfunction: A unique vascular transcriptomic signature.","date":"2018","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/29870805","citation_count":22,"is_preprint":false},{"pmid":"8406478","id":"PMC_8406478","title":"Genetic mapping and evaluation of candidate genes for spasmodic, a neurological mouse mutation with abnormal startle response.","date":"1993","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8406478","citation_count":21,"is_preprint":false},{"pmid":"39625782","id":"PMC_39625782","title":"Vascular smooth muscle cell PRDM16 regulates circadian variation in blood pressure.","date":"2024","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/39625782","citation_count":19,"is_preprint":false},{"pmid":"28931752","id":"PMC_28931752","title":"L-DOPA sensitizes vasomotor tone by modulating the vascular alpha1-adrenergic receptor.","date":"2017","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/28931752","citation_count":19,"is_preprint":false},{"pmid":"31897183","id":"PMC_31897183","title":"POLR1B is upregulated and promotes cell proliferation in non-small cell lung cancer.","date":"2019","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/31897183","citation_count":19,"is_preprint":false},{"pmid":"23695211","id":"PMC_23695211","title":"Sustained in vivo blockade of α₁-adrenergic receptors prevented some of stress-triggered effects on steroidogenic machinery in Leydig cells.","date":"2013","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/23695211","citation_count":18,"is_preprint":false},{"pmid":"35955642","id":"PMC_35955642","title":"Functional Characterization of Human Induced Pluripotent Stem Cell-Derived Endothelial Cells.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35955642","citation_count":17,"is_preprint":false},{"pmid":"22615923","id":"PMC_22615923","title":"Adrenergic alpha-1 pathway is associated with hypertension among Nigerians in a pathway-focused analysis.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22615923","citation_count":17,"is_preprint":false},{"pmid":"34328102","id":"PMC_34328102","title":"QiShenYiQi ameliorates salt-induced hypertensive nephropathy by balancing ADRA1D and SIK1 expression in Dahl salt-sensitive rats.","date":"2021","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/34328102","citation_count":16,"is_preprint":false},{"pmid":"26735301","id":"PMC_26735301","title":"From Bench to Bedside: Attempt to Evaluate Repositioning of Drugs in the Treatment of Metastatic Small Cell Lung Cancer (SCLC).","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26735301","citation_count":16,"is_preprint":false},{"pmid":"17404580","id":"PMC_17404580","title":"Polymorphisms of norepinephrine transporter and adrenergic receptor alpha1D are associated with the response to beta-blockers in dilated cardiomyopathy.","date":"2007","source":"The pharmacogenomics journal","url":"https://pubmed.ncbi.nlm.nih.gov/17404580","citation_count":16,"is_preprint":false},{"pmid":"25108854","id":"PMC_25108854","title":"Effects of colostrum versus formula feeding on hepatic glucocorticoid and α₁- and β₂-adrenergic receptors in neonatal calves and their effect on glucose and lipid metabolism.","date":"2014","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/25108854","citation_count":16,"is_preprint":false},{"pmid":"33862102","id":"PMC_33862102","title":"The mechanisms of action of WeiChang'An Pill (WCAP) treat diarrhoea-predominant irritable bowel syndrome (IBS-D) using network pharmacology approach and in vivo studies.","date":"2021","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33862102","citation_count":16,"is_preprint":false},{"pmid":"26288143","id":"PMC_26288143","title":"Catecholaminergic Gene Polymorphisms Are Associated with GI Symptoms and Morphological Brain Changes in Irritable Bowel Syndrome.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26288143","citation_count":15,"is_preprint":false},{"pmid":"22212102","id":"PMC_22212102","title":"Benzo[α]pyrene-induced anti-depressive-like behaviour in adult female mice: role of monoaminergic systems.","date":"2012","source":"Basic & clinical pharmacology & toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/22212102","citation_count":15,"is_preprint":false},{"pmid":"26617989","id":"PMC_26617989","title":"Individual protomers of a G protein-coupled receptor dimer integrate distinct functional modules.","date":"2015","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/26617989","citation_count":14,"is_preprint":false},{"pmid":"25558416","id":"PMC_25558416","title":"Influence of Panax ginseng on Alpha-Adrenergic Receptor of Benign Prostatic Hyperplasia.","date":"2014","source":"International neurourology journal","url":"https://pubmed.ncbi.nlm.nih.gov/25558416","citation_count":14,"is_preprint":false},{"pmid":"36780704","id":"PMC_36780704","title":"Serum bone remodeling parameters and transcriptome profiling reveal abnormal bone metabolism associated with keel bone fractures in laying hens.","date":"2022","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/36780704","citation_count":13,"is_preprint":false},{"pmid":"40393970","id":"PMC_40393970","title":"Chromogranin A deficiency attenuates tauopathy by altering epinephrine-alpha-adrenergic receptor signaling in PS19 mice.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40393970","citation_count":11,"is_preprint":false},{"pmid":"24440696","id":"PMC_24440696","title":"Developmental genetic profiles of glutamate receptor system, neuromodulator system, protector of normal tissue and mitochondria, and reelin in marmoset cortex: potential molecular mechanisms of pruning phase of spines in primate synaptic formation process during the end of infancy and prepuberty (II).","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/24440696","citation_count":11,"is_preprint":false},{"pmid":"39963073","id":"PMC_39963073","title":"Gastrodin Ameliorates Tau Pathology and BBB Dysfunction in 3xTg-AD Transgenic Mice by Regulating the ADRA1/NF-κB/NLRP3 Pathway to Reduce Neuroinflammation.","date":"2025","source":"Phytotherapy research : PTR","url":"https://pubmed.ncbi.nlm.nih.gov/39963073","citation_count":10,"is_preprint":false},{"pmid":"20110686","id":"PMC_20110686","title":"C2 skeletal myoblast survival, death, proliferation and differentiation: regulation by Adra1d.","date":"2010","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20110686","citation_count":10,"is_preprint":false},{"pmid":"33208818","id":"PMC_33208818","title":"Patulin suppresses α1-adrenergic receptor expression in HEK293 cells.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33208818","citation_count":10,"is_preprint":false},{"pmid":"32061187","id":"PMC_32061187","title":"Epinephrine responsiveness is reduced in livers from trained mice.","date":"2020","source":"Physiological reports","url":"https://pubmed.ncbi.nlm.nih.gov/32061187","citation_count":10,"is_preprint":false},{"pmid":"33352221","id":"PMC_33352221","title":"Terazosin reduces steroidogenic factor 1 and upregulates heat shock protein 90 expression in LH-induced bovine ovarian theca cells.","date":"2020","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33352221","citation_count":10,"is_preprint":false},{"pmid":"39564730","id":"PMC_39564730","title":"Blood Plasma Methylated DNA Markers in the Detection of Lymphoma: Discovery, Validation, and Clinical Pilot.","date":"2024","source":"American journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/39564730","citation_count":9,"is_preprint":false},{"pmid":"31914324","id":"PMC_31914324","title":"Doxazosin treatment in cocaine use disorder: pharmacogenetic response based on an alpha-1 adrenoreceptor subtype D genetic variant.","date":"2020","source":"The American journal of drug and alcohol abuse","url":"https://pubmed.ncbi.nlm.nih.gov/31914324","citation_count":9,"is_preprint":false},{"pmid":"36648147","id":"PMC_36648147","title":"α1 Adrenoreceptor antagonism mitigates extracellular mitochondrial DNA accumulation in lung fibrosis models and in patients with idiopathic pulmonary fibrosis.","date":"2023","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/36648147","citation_count":9,"is_preprint":false},{"pmid":"15503142","id":"PMC_15503142","title":"Haplotype block and superblock structures of the alpha1-adrenergic receptor genes reveal echoes from the chromosomal past.","date":"2004","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/15503142","citation_count":9,"is_preprint":false},{"pmid":"33806345","id":"PMC_33806345","title":"Involvement of the Catecholamine Pathway in Glioblastoma Development.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/33806345","citation_count":8,"is_preprint":false},{"pmid":"37539192","id":"PMC_37539192","title":"Chronic unpredictable stress induces depression/anxiety-related behaviors and alterations of hippocampal monoamine receptor mRNA expression in female mice at different ages.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/37539192","citation_count":8,"is_preprint":false},{"pmid":"36776063","id":"PMC_36776063","title":"Acupuncture Therapy on Dementia: Explained with an Integrated Analysis on Therapeutic Targets and Associated Mechanisms.","date":"2023","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/36776063","citation_count":7,"is_preprint":false},{"pmid":"33898262","id":"PMC_33898262","title":"Molecular basis of ventricular arrhythmogenicity in a Pgc-1α deficient murine model.","date":"2021","source":"Molecular genetics and metabolism reports","url":"https://pubmed.ncbi.nlm.nih.gov/33898262","citation_count":7,"is_preprint":false},{"pmid":"40676669","id":"PMC_40676669","title":"Modulation of neuronal α1-adrenergic receptor reduces tauopathy and neuroinflammation by inhibiting the STING/NF-κB/NLRP3 signaling pathway in Alzheimer's disease mice.","date":"2025","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/40676669","citation_count":6,"is_preprint":false},{"pmid":"36159491","id":"PMC_36159491","title":"Role of sympathetic pathway in light-phase time-restricted feeding-induced blood pressure circadian rhythm alteration.","date":"2022","source":"Frontiers in nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/36159491","citation_count":6,"is_preprint":false},{"pmid":"38729598","id":"PMC_38729598","title":"Genes related to neurotransmitter receptors as potential biomarkers for Alzheimer's disease.","date":"2024","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/38729598","citation_count":5,"is_preprint":false},{"pmid":"28413470","id":"PMC_28413470","title":"Identification of genes associated with the effect of inflammation on the neurotransmission of vascular smooth muscle cell.","date":"2017","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28413470","citation_count":5,"is_preprint":false},{"pmid":"37042962","id":"PMC_37042962","title":"Integrated LC-MS/MS and network pharmacology approach for predictingactive ingredients and pharmacological mechanisms of Tribulus terrestris L. against cardiac diseases.","date":"2023","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/37042962","citation_count":5,"is_preprint":false},{"pmid":"32751869","id":"PMC_32751869","title":"Does the Act of Copulation per se, without Considering Seminal Deposition, Change the Expression of Genes in the Porcine Female Genital Tract?","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32751869","citation_count":5,"is_preprint":false},{"pmid":"40033184","id":"PMC_40033184","title":"Integrated multiomic profiling of tail adipose tissue highlights novel genes, lipids, and metabolites involved in tail fat deposition in sheep.","date":"2025","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/40033184","citation_count":5,"is_preprint":false},{"pmid":"34309518","id":"PMC_34309518","title":"β2-adrenoreceptors control human skin microvascular reactivity.","date":"2021","source":"European journal of dermatology : EJD","url":"https://pubmed.ncbi.nlm.nih.gov/34309518","citation_count":4,"is_preprint":false},{"pmid":"35063136","id":"PMC_35063136","title":"Right ventricular overloading is attenuated in monocrotaline-induced pulmonary hypertension model rats with a disrupted Gpr143 gene, the gene that encodes the 3,4-l-dihydroxyphenyalanine (l-DOPA) receptor.","date":"2021","source":"Journal of pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35063136","citation_count":4,"is_preprint":false},{"pmid":"33402011","id":"PMC_33402011","title":"Development of a Novel SNAP-Epitope Tag/Near-Infrared Imaging Assay to Quantify G Protein-Coupled Receptor Degradation in Human Cells.","date":"2021","source":"SLAS discovery : advancing life sciences R & D","url":"https://pubmed.ncbi.nlm.nih.gov/33402011","citation_count":4,"is_preprint":false},{"pmid":"18204069","id":"PMC_18204069","title":"Cloning, expression and immunolocalization of alpha1-adrenoceptor in different tissues from rhesus monkey and human male reproductive tract.","date":"2008","source":"Molecular human reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/18204069","citation_count":3,"is_preprint":false},{"pmid":"32227770","id":"PMC_32227770","title":"Mechanism underpinning effects of Shichangpu (Rhizoma Acori Tatarinowii) on attention deficit hyperactivity disorder.","date":"2020","source":"Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan","url":"https://pubmed.ncbi.nlm.nih.gov/32227770","citation_count":3,"is_preprint":false},{"pmid":"31783066","id":"PMC_31783066","title":"The temporal pattern of brachial plexus root avulsion-induced lncRNA and mRNA expression prior to the motoneuron loss in the injured spinal cord segments.","date":"2019","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/31783066","citation_count":3,"is_preprint":false},{"pmid":"27061206","id":"PMC_27061206","title":"Exploring novel candidate genes from the Mouse Genome Informatics database: Potential implications for avian migration research.","date":"2016","source":"Integrative zoology","url":"https://pubmed.ncbi.nlm.nih.gov/27061206","citation_count":3,"is_preprint":false},{"pmid":"37571902","id":"PMC_37571902","title":"Functional Involvement of ADRA1D in Cutaneous Melanoma Progression and Angiogenesis.","date":"2023","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/37571902","citation_count":2,"is_preprint":false},{"pmid":"38622006","id":"PMC_38622006","title":"Bioinformatic Identification of Signaling Pathways and Hub Genes in Vascular Dementia.","date":"2024","source":"Actas espanolas de psiquiatria","url":"https://pubmed.ncbi.nlm.nih.gov/38622006","citation_count":2,"is_preprint":false},{"pmid":"35453646","id":"PMC_35453646","title":"Influence of Receptor Polymorphisms on the Response to α-Adrenergic Receptor Blockers in Pheochromocytoma Patients.","date":"2022","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/35453646","citation_count":2,"is_preprint":false},{"pmid":"40170563","id":"PMC_40170563","title":"Exploring the Relationship Between Antipsychotic Drug Target Genes and Epilepsy: Evidence From Food and Drug Administration Adverse Event Reporting System Database and Mendelian Randomization.","date":"2025","source":"Brain and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/40170563","citation_count":2,"is_preprint":false},{"pmid":"26388559","id":"PMC_26388559","title":"Could α1-adrenoceptors and androgen receptors be modified by sexual maturation and testosterone in the rat testicular capsule?","date":"2015","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26388559","citation_count":2,"is_preprint":false},{"pmid":"27913688","id":"PMC_27913688","title":"Left ventricle transcriptomic analysis reveals connective tissue accumulation associates with initial age-dependent decline in V̇o2peak from its lifetime apex.","date":"2016","source":"Physiological genomics","url":"https://pubmed.ncbi.nlm.nih.gov/27913688","citation_count":2,"is_preprint":false},{"pmid":"40398181","id":"PMC_40398181","title":"Lonicerin targets ADRA1D and RSPO3 to ameliorate diabetes-induced vascular injury through Ca2+/Calcineurin/NFAT1-dependent anti-EndMT pathway.","date":"2025","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40398181","citation_count":1,"is_preprint":false},{"pmid":"37394637","id":"PMC_37394637","title":"L-DOPA Receptor GPR143 Functionally Couples with Adrenergic α1B Receptor at the Second Transmembrane Interface.","date":"2023","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/37394637","citation_count":1,"is_preprint":false},{"pmid":"39046281","id":"PMC_39046281","title":"Identification and functionalization of thyrotropin receptor antibodies with different antigenic epitopes.","date":"2024","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/39046281","citation_count":1,"is_preprint":false},{"pmid":"29576394","id":"PMC_29576394","title":"Characterization of a β2 adrenergic receptor protein precursor in the European eel (Anguilla anguilla) and its tissue distribution across silvering.","date":"2018","source":"Marine environmental research","url":"https://pubmed.ncbi.nlm.nih.gov/29576394","citation_count":1,"is_preprint":false},{"pmid":"39546021","id":"PMC_39546021","title":"Revealing the molecular landscape of calcium oxalate renal calculi utilizing a tree shrew model: a transcriptomic analysis of the kidney.","date":"2024","source":"Urolithiasis","url":"https://pubmed.ncbi.nlm.nih.gov/39546021","citation_count":1,"is_preprint":false},{"pmid":"39541744","id":"PMC_39541744","title":"Dissecting the association between blood pressure traits, hypertension, antihypertensive medications and epilepsy: A Mendelian randomization study.","date":"2024","source":"Epilepsy & behavior : E&B","url":"https://pubmed.ncbi.nlm.nih.gov/39541744","citation_count":1,"is_preprint":false},{"pmid":"41120583","id":"PMC_41120583","title":"Osthol ameliorates obesity-associated lipid metabolic disorders by inhibiting ADRA1D-dependent Th17 cell differentiation.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41120583","citation_count":0,"is_preprint":false},{"pmid":"40432440","id":"PMC_40432440","title":"Autoimmune Antibodies in Orthostatic Intolerance Syndromes.","date":"2025","source":"Physiological research","url":"https://pubmed.ncbi.nlm.nih.gov/40432440","citation_count":0,"is_preprint":false},{"pmid":"39149499","id":"PMC_39149499","title":"Chromogranin A Deficiency Attenuates Tauopathy by Altering Epinephrine-Alpha-Adrenergic Receptor Signaling.","date":"2024","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/39149499","citation_count":0,"is_preprint":false},{"pmid":"38915622","id":"PMC_38915622","title":"Chromogranin A (CgA) Deficiency Attenuates Tauopathy by Altering Epinephrine-Alpha-Adrenergic Receptor Signaling.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38915622","citation_count":0,"is_preprint":false},{"pmid":"38806716","id":"PMC_38806716","title":"Patulin alters alpha-adrenergic receptor signalling and induces epigenetic modifications in the kidneys of C57BL/6 mice.","date":"2024","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/38806716","citation_count":0,"is_preprint":false},{"pmid":"36829448","id":"PMC_36829448","title":"Effects of Genetic Mutation Sites in ADR Genes on Modern Chickens Produced and Domesticated by Artificial Selection.","date":"2023","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/36829448","citation_count":0,"is_preprint":false},{"pmid":"41999833","id":"PMC_41999833","title":"Shared and reinforcer-specific alterations in the CRH and noradrenergic systems following short- and long-term withdrawal from cocaine, heroin, and sucrose self-administration.","date":"2026","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/41999833","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.07.25337516","title":"Machine learning to phenotype pain and predict response to pain interventions among young adults with irritable bowel syndrome","date":"2025-10-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.07.25337516","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51876,"output_tokens":5002,"usd":0.115329,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13270,"output_tokens":2995,"usd":0.070612,"stage2_stop_reason":"end_turn"},"total_usd":0.185941,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"ADRA1D undergoes endogenous N-terminal (NT) domain cleavage at Leu90/Val91 in cultured human cells, producing a Δ1-91 isoform. This cleavage is not required for formation of scribble-syntrophin macromolecular complexes, but the Δ1-91 isoform shows greater agonist-stimulated functional responses than wild-type ADRA1D. Mutagenesis of the cleavage site abolished NT processing and reduced agonist responses below wild-type levels.\",\n      \"method\": \"SNAP near-infrared imaging, tandem-affinity purification MS/MS, co-immunoprecipitation, serial truncation mutagenesis, label-free dynamic mass redistribution signaling assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (TAP-MS, Co-IP, mutagenesis, functional signaling assay) in a single rigorous study establishing both the cleavage site and functional consequence\",\n      \"pmids\": [\"27382054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ADRA1D forms an obligate modular homodimer at the plasma membrane that binds the PDZ scaffold proteins syntrophin (SNTA, SNTB1, SNTB2) and scribble (SCRIB) through its C-terminal PDZ ligand. Syntrophins and SCRIB compete for the PDZ ligand and can simultaneously co-exist within the ADRA1D multimer. Syntrophins ensure receptor plasma membrane localization and G-protein coupling, while SCRIB and syntrophins impart divergent pharmacological properties. No other GPCRs among 23 tested with Type I PDZ ligands interacted with syntrophins.\",\n      \"method\": \"Tandem affinity purification/mass spectrometry (TAP/MS), co-immunoprecipitation, dynamic mass redistribution functional assays, biochemical fractionation\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal Co-IP, proteomic TAP/MS, functional pharmacological assay, and negative control (23 other GPCRs), all in one study with multiple orthogonal methods\",\n      \"pmids\": [\"26617989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ADRA1D protein was quantified to have the shortest degradation half-life (t1/2 = 0.52 h) among all nine adrenergic receptor subtypes tested, and degradation occurs primarily through the proteasome (reversed by bortezomib treatment).\",\n      \"method\": \"SNAP-epitope tag/near-infrared imaging cycloheximide-chase degradation assay, proteasome inhibitor (bortezomib) treatment, 96-well plate format\",\n      \"journal\": \"SLAS discovery : advancing life sciences R & D\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative CHX-chase assay with proteasome inhibitor validation in a single lab, two complementary formats (PAGE and 96-well)\",\n      \"pmids\": [\"33402011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRDM16, a transcription factor expressed in vascular smooth muscle cells (VSMCs), directly regulates the transcription of Adra1d. VSMC-specific Prdm16 knockout mice show significantly lower blood pressure during the active period and reduced mesenteric artery contraction in response to phenylephrine (an α1-adrenergic agonist), resulting in aberrant blood pressure circadian variation. PRDM16 also regulates clock genes (particularly Npas2) that control BP circadian variation.\",\n      \"method\": \"VSMC-specific conditional knockout mice, telemetric blood pressure measurement, ex vivo mesenteric artery myography with phenylephrine, transcriptional target identification\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO with functional vascular phenotype, blood pressure telemetry, and ex vivo functional assay, establishing ADRA1D as a direct transcriptional target of PRDM16\",\n      \"pmids\": [\"39625782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Adra1d expression in C2 skeletal myoblasts is upregulated under survival conditions (IGF-I rescue of high-dose TNF-α-induced death) and downregulated under apoptotic conditions. siRNA knockdown of Adra1d resulted in significantly higher cell death across all incubation conditions, establishing that Adra1d expression is essential for skeletal myoblast survival.\",\n      \"method\": \"Insulin signaling array, qRT-PCR, siRNA gene silencing, cell viability assays under defined TNF-α/IGF-I conditions\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with quantified phenotypic readout under multiple conditions, single lab\",\n      \"pmids\": [\"20110686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Patulin (PAT) exposure in HEK293 cells decreased ADRA1D mRNA and protein expression and altered downstream AMPK pathway signaling (ERK1/2, PI3K/Akt). Molecular docking indicated direct interaction of PAT with ADRA1A (and PRKAG3). NAC (antioxidant) ameliorated PAT-induced suppression of α1-AR, while BSO (GSH inhibitor) potentiated it, linking oxidative stress to ADRA1D downregulation.\",\n      \"method\": \"qPCR, western blotting, molecular docking, pharmacological modulation (Epi, metformin, BSO, NAC)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, no mutagenesis or rescue experiment; molecular docking is computational; mechanistic pathway placement partially inferred\",\n      \"pmids\": [\"33208818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Alzheimer's disease mouse models (3xTg-AD), ADRA1 expression and epinephrine (EPI) levels are elevated. Neuronal ADRA1D knockdown (via intracerebroventricular AAV) suppressed STING/NF-κB/NLRP3 pathway activation, ameliorated tau hyperphosphorylation, and improved cognitive function. ADRA1D overexpression in wild-type mice induced tauopathy and neuroinflammation. Mechanistically, ADRA1D interacts with CXCR4 to form heterodimers, triggering cytoplasmic Ca2+ overload and STING/NF-κB/NLRP3 pathway activation.\",\n      \"method\": \"AAV-mediated neuronal ADRA1D knockdown and overexpression, co-immunoprecipitation, calcium flux assays, pharmacological antagonists, Western blot, behavioral testing\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo AAV KD/OE with defined molecular pathway, Co-IP for CXCR4 heterodimer, Ca2+ flux assays; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40676669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In 3xTg-AD mice, gastrodin inhibits the ADRA1/NF-κB/NLRP3 pathway, reducing tau phosphorylation and neuroinflammation. Lentiviral overexpression of ADRA1 in vitro reversed gastrodin's suppression of NF-κB/NLRP3 activation and inflammatory cytokine release (IL-1β, IL-18). Aβ42-induced upregulation of ADRA1/NF-κB/NLRP3 was inhibited by gastrodin in SH-SY5Y cells.\",\n      \"method\": \"Lentiviral ADRA1 overexpression, Western blot, immunohistochemistry, ELISA, in vitro Aβ42 cell model\",\n      \"journal\": \"Phytotherapy research : PTR\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanistic placement relies on overexpression rescue without direct receptor mutagenesis or direct binding assay\",\n      \"pmids\": [\"39963073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Lonicerin reduces high glucose-induced upregulation of ADRA1D in human aortic endothelial cells (HAECs), leading to decreased cytoplasmic Ca2+ levels, inhibition of calcineurin activity, NFAT1 phosphorylation, and prevention of endothelial-to-mesenchymal transition (EndMT). EC-specific overexpression of ADRA1D negated the inhibitory effects of lonicerin on EndMT and its therapeutic impact on diabetic vascular injury, establishing ADRA1D as a proximal mediator of the Ca2+/Calcineurin/NFAT1-dependent EndMT pathway.\",\n      \"method\": \"RNAi, plasmid overexpression, Western blot, qRT-PCR, immunofluorescence, flow cytometry, calcineurin activity assay, RNA sequencing, STZ-induced diabetic mouse model\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression rescue in both in vitro and in vivo (EC-specific), with Ca2+ flux and calcineurin activity measured; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40398181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In a bleomycin mouse lung fibrosis model, noradrenaline from local adrenergic nerves (not adrenal sources) drives emergence of an αSMA+ fibroblast population expressing ADRA1D. Therapeutic delivery of the α1 adrenoreceptor antagonist terazosin reversed fibroblast accumulation and suppressed extracellular mitochondrial DNA (mtDNA) accumulation. In cultured normal human lung fibroblasts, costimulation with TGFβ1 and NA induced ADRA1D expression, ACTA2 upregulation, and extracellular mtDNA release, all opposed by terazosin.\",\n      \"method\": \"Surgical adrenergic nerve ablation vs. adrenal resection in bleomycin model, pharmacological antagonism (terazosin), cultured human lung fibroblasts with TGFβ1/NA stimulation, αSMA/ADRA1D immunostaining\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — nerve ablation and pharmacological experiments in vivo plus in vitro fibroblast model, multiple readouts; single lab\",\n      \"pmids\": [\"36648147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In an in vitro OGD (oxygen-glucose deprivation) model of vascular dementia using PC12 cells, ADRA1D overexpression decreased apoptosis and lowered intracellular Ca2+ levels, while ADRA1D knockdown increased apoptosis and elevated Ca2+. Mechanistically, ADRA1D overexpression reduced PLCβ and IP3R expression, suggesting ADRA1D modulates Ca2+ homeostasis via the PLCβ/IP3R pathway.\",\n      \"method\": \"OGD PC12 cell model, lentiviral overexpression and siRNA knockdown of ADRA1D, TUNEL assay, RT-qPCR, Western blot, Fluo-3 AM Ca2+ imaging\",\n      \"journal\": \"Actas espanolas de psiquiatria\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, in vitro only, pathway inference from downstream expression changes without direct binding or kinetic assays\",\n      \"pmids\": [\"38622006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In chromogranin A (CgA) knockout/PS19 tauopathy mice, cortical epinephrine (EPI) levels and Adra1 expression (elevated in PS19 mice relative to WT) were reduced back to near-normal. Treatment of WT hippocampal organotypic slice cultures with EPI or an Adra1 agonist promoted tau hyperphosphorylation and neurofibrillary tangle formation, while an Adra1 antagonist inhibited these effects, establishing a functional EPI-Adra1 signaling axis in tau pathogenesis.\",\n      \"method\": \"Transgenic mouse models (CgA-KO/PS19), transcriptomic and metabolite analysis, hippocampal organotypic slice culture pharmacology (EPI, Adra1 agonist, Adra1 antagonist), immunohistochemistry\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological gain- and loss-of-function in ex vivo slice culture with functional tau readout, plus in vivo genetic model; single lab, multiple methods\",\n      \"pmids\": [\"40393970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Osthol (OST) downregulates ADRA1D expression in obese mice, suppressing Th17 differentiation (reduced CD4+IL-17A+ and CD4+RORγt+ cells). ADRA1D overexpression in vitro and in vivo partially reversed OST-mediated suppression of Th17 polarization, expression of lipogenic genes (FASN, PPARγ), and lipid droplet accumulation, establishing ADRA1D as a mediator of Th17 differentiation linked to obesity-associated immunometabolic dysregulation.\",\n      \"method\": \"HFD mouse model, in vitro Th17 differentiation (primary murine CD4+ T cells), ADRA1D overexpression (cells and mice), flow cytometry, ELISA, RT-qPCR, Western blot\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression rescue establishes ADRA1D dependence but mechanism of ADRA1D action on Th17 differentiation is not directly resolved; single lab\",\n      \"pmids\": [\"41120583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADRA1D mRNA and protein are downregulated in the injured spinal cord following brachial plexus root avulsion. The lncRNA MRAK034299, which targets Adra1d, is also downregulated post-avulsion, suggesting a lncRNA-mediated epigenetic mechanism contributes to reduced ADRA1D expression in motoneuron injury context.\",\n      \"method\": \"Microarray lncRNA/mRNA profiling, qRT-PCR validation, Western blot, immunofluorescence, in vivo rat brachial plexus avulsion model\",\n      \"journal\": \"Neurochemistry international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-expression of lncRNA and mRNA changes validated but causal mechanism not directly tested; single lab\",\n      \"pmids\": [\"31783066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"L-DOPA sensitizes vascular ADRA1 (alpha-1 adrenergic receptor) signaling in vascular smooth muscle cells (VSMCs) via the L-DOPA receptor GPR143. Specific knockout of Gpr143 in VSMCs attenuated phenylephrine-induced blood pressure elevation. L-DOPA enhanced phenylephrine-induced vasoconstriction and intracellular Ca2+ responses in vitro. Phenylephrine-augmented ERK phosphorylation was present in WT but not Gpr143-/y VSMCs.\",\n      \"method\": \"Gpr143 whole-body and VSMC-specific knockout mice, intravenous phenylephrine infusion with telemetric blood pressure, in vitro VSMC Ca2+ imaging, ERK phosphorylation assay\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO with defined vascular functional phenotype and in vitro mechanistic validation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"28931752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"L-DOPA receptor GPR143 physically interacts with ADRA1B at the second transmembrane (TM2) domain interface. A synthetic TAT-TM2 peptide disrupted the GPR143-ADRA1B interaction (co-immunoprecipitation) and suppressed GPR143-augmented phenylephrine-induced ERK phosphorylation in HEK293T cells co-expressing ADRA1B and GPR143.\",\n      \"method\": \"Chimeric receptor analysis (TM domain swapping), co-immunoprecipitation, TAT-peptide disruption, ERK phosphorylation assay in HEK293T cells\",\n      \"journal\": \"Biological & pharmaceutical bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chimeric analysis and Co-IP establish TM2 as the interaction interface with functional validation via peptide disruption; single lab, multiple methods. Note: this paper concerns ADRA1B primarily, with functional relevance to the ADRA1 subfamily including ADRA1D signaling context.\",\n      \"pmids\": [\"37394637\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADRA1D is a G protein-coupled α1-adrenergic receptor that localizes to the plasma membrane as an obligate modular homodimer scaffolded by PDZ proteins syntrophin and scribble; it undergoes endogenous N-terminal cleavage at Leu90/Val91 to generate a Δ1-91 isoform with enhanced agonist-stimulated signaling, is a direct transcriptional target of PRDM16 in vascular smooth muscle cells controlling blood pressure circadian rhythm, couples to Ca2+/calcineurin/NFAT1 and STING/NF-κB/NLRP3 inflammatory pathways in endothelial and neuronal cells, is sensitized by L-DOPA/GPR143 signaling to amplify vasoconstriction, and is essential for skeletal myoblast survival, with the shortest proteasome-dependent degradation half-life among all adrenergic receptor subtypes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADRA1D is a plasma-membrane G protein-coupled α1-adrenergic receptor that organizes into an obligate modular homodimer scaffolded through its C-terminal Type I PDZ ligand by the PDZ proteins syntrophin (SNTA, SNTB1, SNTB2) and scribble (SCRIB), which compete for the ligand yet can coexist within the multimer; syntrophins drive plasma-membrane localization and G-protein coupling while SCRIB and syntrophins impart divergent pharmacology [#1]. The receptor undergoes endogenous N-terminal cleavage at Leu90/Val91 to generate a Δ1-91 isoform with enhanced agonist-stimulated signaling, and abolishing this processing reduces responsiveness below wild-type [#0]. ADRA1D is among the most short-lived adrenergic receptors, turning over rapidly via the proteasome [#2]. In vascular smooth muscle, Adra1d is a direct transcriptional target of PRDM16, and loss of this regulation lowers blood pressure during the active period and blunts phenylephrine-induced arterial contraction, linking the receptor to circadian blood-pressure control [#3]; its vasoconstrictor signaling is further sensitized by L-DOPA acting through GPR143 to amplify phenylephrine-induced Ca2+ and ERK responses [#14]. Across endothelial, neuronal, and immune contexts, ADRA1D acts as a proximal driver of intracellular Ca2+-dependent signaling — engaging the Ca2+/calcineurin/NFAT1 axis to promote endothelial-to-mesenchymal transition [#8] and, via heterodimerization with CXCR4, triggering Ca2+ overload and STING/NF-κB/NLRP3 activation that promotes tau hyperphosphorylation and neuroinflammation [#6]. ADRA1D expression is also required for skeletal myoblast survival [#4].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that ADRA1D expression has a cell-survival function beyond classical vasoactive signaling, in skeletal muscle.\",\n      \"evidence\": \"siRNA knockdown with viability readout under TNF-α/IGF-I conditions in C2 myoblasts\",\n      \"pmids\": [\"20110686\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream survival pathway not defined\", \"No receptor-domain or signaling mechanism linked to the phenotype\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the structural and scaffolding architecture of the receptor, answering how ADRA1D reaches the membrane and couples to G proteins.\",\n      \"evidence\": \"TAP/MS, reciprocal Co-IP, DMR functional assays with 23-GPCR negative control\",\n      \"pmids\": [\"26617989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the homodimer or PDZ interface\", \"Functional consequence of SCRIB vs syntrophin competition not fully resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified an endogenous N-terminal cleavage event that generates a signaling-enhanced receptor isoform, revealing post-translational tuning of agonist responsiveness.\",\n      \"evidence\": \"NIR imaging, TAP-MS/MS, serial truncation and cleavage-site mutagenesis, DMR signaling assays in human cells\",\n      \"pmids\": [\"27382054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease responsible for Leu90/Val91 cleavage unidentified\", \"Physiological regulation of cleavage in vivo unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed that ADRA1 vasoconstrictor signaling is sensitized by L-DOPA through GPR143, connecting receptor function to blood-pressure regulation.\",\n      \"evidence\": \"Gpr143 whole-body and VSMC-specific KO mice, telemetric BP, VSMC Ca2+ imaging, ERK phosphorylation\",\n      \"pmids\": [\"28931752\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ADRA1D-GPR143 interaction not demonstrated (subtype specificity within ADRA1 unresolved)\", \"Mechanism of sensitization at the receptor level undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Quantified ADRA1D turnover, establishing it as the shortest-lived adrenergic receptor and proteasome-dependent for degradation.\",\n      \"evidence\": \"SNAP/NIR cycloheximide-chase degradation assay with bortezomib in 96-well and PAGE formats\",\n      \"pmids\": [\"33402011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase and degradation signal not identified\", \"Single-lab measurement in heterologous cells\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapped the TM2 interface used by GPR143 to augment ADRA1-subfamily signaling, providing a molecular handle for the sensitization mechanism.\",\n      \"evidence\": \"Chimeric TM-domain swapping, Co-IP, TAT-TM2 peptide disruption, ERK assays (study centered on ADRA1B)\",\n      \"pmids\": [\"37394637\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct relevance to ADRA1D vs ADRA1B not established\", \"No structural validation of the interface\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified ADRA1D as a direct transcriptional target of PRDM16 in VSMCs controlling circadian blood-pressure variation.\",\n      \"evidence\": \"VSMC-specific Prdm16 KO mice, BP telemetry, ex vivo mesenteric artery myography with phenylephrine\",\n      \"pmids\": [\"39625782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PRDM16 occupancy at the Adra1d locus not detailed here\", \"Relative contribution of Adra1d vs clock-gene regulation to phenotype unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed ADRA1D as a proximal Ca2+-driven effector across endothelial and neuronal pathology, signaling through calcineurin/NFAT1 (EndMT) and CXCR4-heterodimer/STING/NF-κB/NLRP3 (tauopathy/neuroinflammation).\",\n      \"evidence\": \"EC- and neuron-specific overexpression/knockdown in vivo and in vitro, Co-IP for CXCR4 heterodimer, Ca2+ flux and calcineurin assays, behavioral and tau readouts\",\n      \"pmids\": [\"40398181\", \"40676669\", \"40393970\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the same receptor pool drives both calcineurin/NFAT1 and STING/NLRP3 outputs is unclear\", \"ADRA1D-CXCR4 heterodimer requires reciprocal structural validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the receptor's structural features (cleavage, dimerization, PDZ scaffolding, rapid turnover) mechanistically dictate which downstream Ca2+ pathway is engaged in a given tissue remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking receptor processing/scaffolding to pathway selection\", \"Protease and E3 ligase identities unknown\", \"Subtype-specific roles vs ADRA1A/ADRA1B not delineated in shared pathways\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0004930\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SNTA1\", \"SNTB1\", \"SNTB2\", \"SCRIB\", \"GPR143\", \"CXCR4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}