{"gene":"ADRA2B","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2005,"finding":"The common del301-303 (9-nucleotide deletion, +901 Del) variant in the ADRA2B coding region results in markedly decreased receptor desensitization in vitro, as established by functional assays, though it does not alter vascular sensitivity to dexmedetomidine in vivo.","method":"In vitro receptor desensitization assay; in vivo dorsal hand vein pharmacodynamic study with selective α2-agonist dexmedetomidine","journal":"Pharmacogenetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro functional assay referenced from prior work, confirmed in vivo pharmacodynamic study; single lab","pmids":["15900214"],"is_preprint":false},{"year":2009,"finding":"A novel 12-nucleotide insertion polymorphism at position -4825 in the ADRA2B promoter region is in complete linkage disequilibrium with the +901 Del coding variant and reduces ADRA2B transcriptional activity in vitro. Electrophoretic mobility shift assays showed this insertion alters the pattern of nuclear protein/transcription factor binding at the promoter.","method":"Luciferase reporter transfection assay in multiple cell lines; electrophoretic mobility shift assay (EMSA); genotyping of 71 individuals","journal":"Biochemical pharmacology","confidence":"High","confidence_rationale":"Tier 1 — direct functional reporter assay plus EMSA with two orthogonal methods in a single study demonstrating reduced transcriptional activity and altered transcription factor binding","pmids":["19728989"],"is_preprint":false},{"year":2022,"finding":"ADRA2B (α2B adrenoceptor) was identified as a molecular target of the insecticide carbaryl; carbaryl acts as an antagonist at ADRA2B, and pharmacological antagonism of ADRA2B (mimicked by yohimbine) increases heart rate and impairs behavior in zebrafish larvae, establishing ADRA2B antagonism as a molecular initiating event in carbaryl toxicity.","method":"In silico target prediction followed by in vitro validation; pharmacological antagonism in zebrafish larvae (heart rate measurement, behavioral assays); comparison with prototypic ADRA2B antagonist yohimbine","journal":"Journal of hazardous materials","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro validation plus in vivo pharmacological rescue with selective antagonist in zebrafish; single lab","pmids":["35248961"],"is_preprint":false}],"current_model":"ADRA2B encodes the α2B-adrenoceptor, a GPCR mediating vasoconstriction and norepinephrine signaling; a common 9-nucleotide coding deletion (+901 Del) markedly reduces receptor desensitization in vitro and is in complete linkage with a promoter insertion that reduces transcriptional activity by altering transcription factor binding, while receptor antagonism increases heart rate and impairs behavior, collectively establishing roles for ADRA2B in vascular tone regulation, receptor desensitization, and transcriptional control of adrenergic signaling."},"narrative":{"teleology":[{"year":2005,"claim":"Functional characterization of the common +901 Del coding variant established that it impairs agonist-induced desensitization of the α2B-adrenoceptor in vitro, although this did not translate into altered vascular sensitivity to a selective agonist in vivo, raising the question of whether additional regulatory mechanisms buffer the functional consequence.","evidence":"In vitro desensitization assays combined with in vivo dorsal hand vein pharmacodynamic study using dexmedetomidine in human subjects","pmids":["15900214"],"confidence":"Medium","gaps":["Single-lab pharmacodynamic study; no independent replication of the in vivo vascular finding","Mechanism by which the deletion impairs desensitization (e.g., altered phosphorylation, arrestin binding) not defined","Tissue-specific relevance of the desensitization defect beyond the vascular bed not explored"]},{"year":2009,"claim":"Discovery of a promoter insertion polymorphism in complete linkage disequilibrium with the +901 Del coding variant resolved why the coding variant alone may not fully predict phenotypic effects: the linked promoter insertion reduces ADRA2B transcriptional activity and alters transcription factor binding, meaning carriers harbor coupled transcriptional and post-translational regulatory changes.","evidence":"Luciferase reporter assays in multiple cell lines; EMSA demonstrating altered nuclear protein binding; genotyping of 71 individuals for linkage analysis","pmids":["19728989"],"confidence":"High","gaps":["Identity of the transcription factors whose binding is altered by the promoter insertion not determined","Net in vivo effect of the opposing regulatory changes (reduced transcription vs. reduced desensitization) on receptor density and signaling output unknown","No chromatin-level or endogenous gene expression data confirming the reporter findings"]},{"year":2022,"claim":"Identification of ADRA2B as a molecular target of the insecticide carbaryl, acting as an antagonist, established that ADRA2B blockade is sufficient to increase heart rate and impair larval behavior, providing in vivo evidence for ADRA2B's role in cardiovascular and neurobehavioral regulation.","evidence":"In silico target prediction with in vitro validation; pharmacological antagonism in zebrafish larvae using carbaryl and the prototypic antagonist yohimbine with heart rate and behavioral readouts","pmids":["35248961"],"confidence":"Medium","gaps":["Zebrafish model; relevance to mammalian cardiovascular physiology not directly demonstrated","Selectivity of carbaryl for ADRA2B over other adrenergic receptor subtypes not fully resolved","Downstream intracellular signaling pathways mediating the heart rate and behavioral effects not characterized"]},{"year":null,"claim":"The identity of transcription factors binding the ADRA2B promoter insertion site, the structural basis of impaired desensitization by the +901 Del variant, and the integrated physiological impact of the linked coding–promoter haplotype on adrenergic tone in mammalian systems remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or cryo-EM model of the α2B-adrenoceptor with or without the deletion","No mammalian knockout or knock-in studies dissecting the individual contributions of the promoter and coding variants","Downstream G-protein coupling specificity and arrestin recruitment kinetics for ADRA2B not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2]}],"complexes":[],"partners":[],"other_free_text":[]},"mechanistic_narrative":"ADRA2B encodes the α2B-adrenergic receptor, a G protein-coupled receptor that mediates sympathetic signaling and contributes to cardiovascular regulation; pharmacological antagonism of ADRA2B increases heart rate and impairs behavior in zebrafish larvae [PMID:35248961]. A common 9-nucleotide in-frame deletion (+901 Del) in the coding region markedly reduces agonist-induced receptor desensitization in vitro, and this variant is in complete linkage disequilibrium with a 12-nucleotide promoter insertion at position −4825 that reduces transcriptional activity by altering nuclear protein binding, indicating coupled cis-regulatory and coding-level modulation of receptor function [PMID:15900214, PMID:19728989]."},"prefetch_data":{"uniprot":{"accession":"P18089","full_name":"Alpha-2B adrenergic receptor","aliases":["Alpha-2 adrenergic receptor subtype C2","Alpha-2B adrenoreceptor","Alpha-2B adrenoceptor","Alpha-2BAR"],"length_aa":450,"mass_kda":50.0,"function":"Alpha-2 adrenergic receptors are G protein-coupled receptors for catecholamines that activate G(i/o) protein pathway, thereby promoting adenylyl cyclase inhibition, ERK1/2 stimulation, and voltage-gated calcium channels suppression (PubMed:11056163, PubMed:2164221, PubMed:2172775, PubMed:23105096, PubMed:26811329). Control a variety of physiological processes, such as regulation of blood pressure, lipolysis and insulin release (PubMed:2164221). The rank order of potency for agonists of ADRA2B is clonidine > norepinephrine > epinephrine = oxymetazoline > dopamine > p-tyramine = phenylephrine > serotonin > p-synephrine / p-octopamine. For antagonists, the rank order is yohimbine > chlorpromazine > phentolamine > mianserine > spiperone > prazosin > alprenolol > propanolol > pindolol (PubMed:2164221, PubMed:2172775)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P18089/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADRA2B","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADRA2B","total_profiled":1310},"omim":[{"mim_id":"620890","title":"GROWTH HORMONE-REGULATED TBC PROTEIN 1; GRTP1","url":"https://www.omim.org/entry/620890"},{"mim_id":"616712","title":"START DOMAIN-CONTAINING PROTEIN 7; STARD7","url":"https://www.omim.org/entry/616712"},{"mim_id":"607876","title":"EPILEPSY, FAMILIAL ADULT MYOCLONIC, 2; FAME2","url":"https://www.omim.org/entry/607876"},{"mim_id":"104260","title":"ALPHA-2B-ADRENERGIC RECEPTOR; ADRA2B","url":"https://www.omim.org/entry/104260"},{"mim_id":"104250","title":"ALPHA-2C-ADRENERGIC RECEPTOR; ADRA2C","url":"https://www.omim.org/entry/104250"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ADRA2B"},"hgnc":{"alias_symbol":["ADRARL1"],"prev_symbol":["ADRA2L1","ADRA2RL1"]},"alphafold":{"accession":"P18089","domains":[{"cath_id":"1.20.1070.10","chopping":"10-153_160-204_357-443","consensus_level":"high","plddt":90.118,"start":10,"end":443}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P18089","model_url":"https://alphafold.ebi.ac.uk/files/AF-P18089-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P18089-F1-predicted_aligned_error_v6.png","plddt_mean":71.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADRA2B","jax_strain_url":"https://www.jax.org/strain/search?query=ADRA2B"},"sequence":{"accession":"P18089","fasta_url":"https://rest.uniprot.org/uniprotkb/P18089.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P18089/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P18089"}},"corpus_meta":[{"pmid":"15900214","id":"PMC_15900214","title":"Variation in the alpha2B-adrenergic receptor gene (ADRA2B) and its relationship to vascular response in vivo.","date":"2005","source":"Pharmacogenetics and genomics","url":"https://pubmed.ncbi.nlm.nih.gov/15900214","citation_count":31,"is_preprint":false},{"pmid":"23583499","id":"PMC_23583499","title":"ADRA2B genotype modulates effects of acute psychosocial stress on emotional memory retrieval in healthy young men.","date":"2013","source":"Neurobiology of learning and memory","url":"https://pubmed.ncbi.nlm.nih.gov/23583499","citation_count":30,"is_preprint":false},{"pmid":"17277585","id":"PMC_17277585","title":"Physical activity, diet, and incident diabetes in relation to an ADRA2B polymorphism.","date":"2007","source":"Medicine and science in sports and exercise","url":"https://pubmed.ncbi.nlm.nih.gov/17277585","citation_count":26,"is_preprint":false},{"pmid":"24149058","id":"PMC_24149058","title":"Deletion variant in the ADRA2B gene increases coupling between emotional responses at encoding and later retrieval of emotional memories.","date":"2013","source":"Neurobiology of learning and memory","url":"https://pubmed.ncbi.nlm.nih.gov/24149058","citation_count":22,"is_preprint":false},{"pmid":"35248961","id":"PMC_35248961","title":"Environmental levels of carbaryl impair zebrafish larvae behaviour: The potential role of ADRA2B and HTR2B.","date":"2022","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/35248961","citation_count":20,"is_preprint":false},{"pmid":"29751052","id":"PMC_29751052","title":"ADRA2B deletion variant and enhanced cognitive processing of emotional information: A meta-analytical review.","date":"2018","source":"Neuroscience and biobehavioral reviews","url":"https://pubmed.ncbi.nlm.nih.gov/29751052","citation_count":16,"is_preprint":false},{"pmid":"26899992","id":"PMC_26899992","title":"The modulating role of ADRA2B in emotional working memory: Attending the negative but remembering the positive.","date":"2016","source":"Neurobiology of learning and memory","url":"https://pubmed.ncbi.nlm.nih.gov/26899992","citation_count":15,"is_preprint":false},{"pmid":"20401689","id":"PMC_20401689","title":"Lifestyle modifies the relationship between body composition and adrenergic receptor genetic polymorphisms, ADRB2, ADRB3 and ADRA2B: a secondary analysis of a randomized controlled trial of physical activity among postmenopausal women.","date":"2010","source":"Behavior genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20401689","citation_count":15,"is_preprint":false},{"pmid":"25127926","id":"PMC_25127926","title":"ADRA2B genotype differentially modulates stress-induced neural activity in the amygdala and hippocampus during emotional memory retrieval.","date":"2014","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25127926","citation_count":14,"is_preprint":false},{"pmid":"16269962","id":"PMC_16269962","title":"Cardiovascular and metabolic phenotypes in relation to the ADRA2B insertion/deletion polymorphism in a Chinese population.","date":"2005","source":"Journal of hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/16269962","citation_count":13,"is_preprint":false},{"pmid":"21965191","id":"PMC_21965191","title":"Influence of COMT val158met and ADRA2B deletion polymorphisms on recollection and familiarity components of human emotional memory.","date":"2011","source":"Journal of psychopharmacology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/21965191","citation_count":11,"is_preprint":false},{"pmid":"28254464","id":"PMC_28254464","title":"ADRA2B deletion variant influences time-dependent effects of pre-learning stress on long-term memory.","date":"2017","source":"Neurobiology of learning and memory","url":"https://pubmed.ncbi.nlm.nih.gov/28254464","citation_count":11,"is_preprint":false},{"pmid":"19593211","id":"PMC_19593211","title":"Chromosome 2q12, the ADRA2B I/D polymorphism and metabolic syndrome.","date":"2009","source":"Journal of hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/19593211","citation_count":7,"is_preprint":false},{"pmid":"19728989","id":"PMC_19728989","title":"Identification of a novel 12-nucleotide insertion polymorphism in the promoter region of ADRA2B: full linkage with the 9-nucleotide deletion in the coding region and influence on transcriptional activity.","date":"2009","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/19728989","citation_count":7,"is_preprint":false},{"pmid":"16336817","id":"PMC_16336817","title":"ADRA2B gene insertion/deletion polymorphism and artery compliance.","date":"2005","source":"Chinese medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/16336817","citation_count":4,"is_preprint":false},{"pmid":"20651814","id":"PMC_20651814","title":"Lack of association between ADRA2B-4825 gene insertion/deletion polymorphism and migraine in Chinese Han population.","date":"2010","source":"Neuroscience bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/20651814","citation_count":3,"is_preprint":false},{"pmid":"28697904","id":"PMC_28697904","title":"The ADRA2B gene in the production of false memories for affective information in healthy female volunteers.","date":"2017","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/28697904","citation_count":3,"is_preprint":false},{"pmid":"25325286","id":"PMC_25325286","title":"A 9-nucleotide Ins/Del in ADRA2B modulates orientation of attention to facial expressions and emotional words.","date":"2014","source":"Behavioural pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25325286","citation_count":3,"is_preprint":false},{"pmid":"37525034","id":"PMC_37525034","title":"ADRA2B and HTR1A: An Updated Study of the Biogenic Amine Receptors Reveals Novel Conserved Motifs Which Play Key Role in Mental Disorders.","date":"2023","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/37525034","citation_count":3,"is_preprint":false},{"pmid":"38571653","id":"PMC_38571653","title":"Identification of a de novo CACNA1B variant and a start-loss ADRA2B variant in paroxysmal kinesigenic dyskinesia.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38571653","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10620,"output_tokens":875,"usd":0.022492},"stage2":{"model":"claude-opus-4-6","input_tokens":4066,"output_tokens":1296,"usd":0.079095},"total_usd":0.101587,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"The common del301-303 (9-nucleotide deletion, +901 Del) variant in the ADRA2B coding region results in markedly decreased receptor desensitization in vitro, as established by functional assays, though it does not alter vascular sensitivity to dexmedetomidine in vivo.\",\n      \"method\": \"In vitro receptor desensitization assay; in vivo dorsal hand vein pharmacodynamic study with selective α2-agonist dexmedetomidine\",\n      \"journal\": \"Pharmacogenetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro functional assay referenced from prior work, confirmed in vivo pharmacodynamic study; single lab\",\n      \"pmids\": [\"15900214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A novel 12-nucleotide insertion polymorphism at position -4825 in the ADRA2B promoter region is in complete linkage disequilibrium with the +901 Del coding variant and reduces ADRA2B transcriptional activity in vitro. Electrophoretic mobility shift assays showed this insertion alters the pattern of nuclear protein/transcription factor binding at the promoter.\",\n      \"method\": \"Luciferase reporter transfection assay in multiple cell lines; electrophoretic mobility shift assay (EMSA); genotyping of 71 individuals\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct functional reporter assay plus EMSA with two orthogonal methods in a single study demonstrating reduced transcriptional activity and altered transcription factor binding\",\n      \"pmids\": [\"19728989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ADRA2B (α2B adrenoceptor) was identified as a molecular target of the insecticide carbaryl; carbaryl acts as an antagonist at ADRA2B, and pharmacological antagonism of ADRA2B (mimicked by yohimbine) increases heart rate and impairs behavior in zebrafish larvae, establishing ADRA2B antagonism as a molecular initiating event in carbaryl toxicity.\",\n      \"method\": \"In silico target prediction followed by in vitro validation; pharmacological antagonism in zebrafish larvae (heart rate measurement, behavioral assays); comparison with prototypic ADRA2B antagonist yohimbine\",\n      \"journal\": \"Journal of hazardous materials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro validation plus in vivo pharmacological rescue with selective antagonist in zebrafish; single lab\",\n      \"pmids\": [\"35248961\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADRA2B encodes the α2B-adrenoceptor, a GPCR mediating vasoconstriction and norepinephrine signaling; a common 9-nucleotide coding deletion (+901 Del) markedly reduces receptor desensitization in vitro and is in complete linkage with a promoter insertion that reduces transcriptional activity by altering transcription factor binding, while receptor antagonism increases heart rate and impairs behavior, collectively establishing roles for ADRA2B in vascular tone regulation, receptor desensitization, and transcriptional control of adrenergic signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ADRA2B encodes the α2B-adrenergic receptor, a G protein-coupled receptor that mediates sympathetic signaling and contributes to cardiovascular regulation; pharmacological antagonism of ADRA2B increases heart rate and impairs behavior in zebrafish larvae [PMID:35248961]. A common 9-nucleotide in-frame deletion (+901 Del) in the coding region markedly reduces agonist-induced receptor desensitization in vitro, and this variant is in complete linkage disequilibrium with a 12-nucleotide promoter insertion at position −4825 that reduces transcriptional activity by altering nuclear protein binding, indicating coupled cis-regulatory and coding-level modulation of receptor function [PMID:15900214, PMID:19728989].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Functional characterization of the common +901 Del coding variant established that it impairs agonist-induced desensitization of the α2B-adrenoceptor in vitro, although this did not translate into altered vascular sensitivity to a selective agonist in vivo, raising the question of whether additional regulatory mechanisms buffer the functional consequence.\",\n      \"evidence\": \"In vitro desensitization assays combined with in vivo dorsal hand vein pharmacodynamic study using dexmedetomidine in human subjects\",\n      \"pmids\": [\"15900214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab pharmacodynamic study; no independent replication of the in vivo vascular finding\",\n        \"Mechanism by which the deletion impairs desensitization (e.g., altered phosphorylation, arrestin binding) not defined\",\n        \"Tissue-specific relevance of the desensitization defect beyond the vascular bed not explored\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Discovery of a promoter insertion polymorphism in complete linkage disequilibrium with the +901 Del coding variant resolved why the coding variant alone may not fully predict phenotypic effects: the linked promoter insertion reduces ADRA2B transcriptional activity and alters transcription factor binding, meaning carriers harbor coupled transcriptional and post-translational regulatory changes.\",\n      \"evidence\": \"Luciferase reporter assays in multiple cell lines; EMSA demonstrating altered nuclear protein binding; genotyping of 71 individuals for linkage analysis\",\n      \"pmids\": [\"19728989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the transcription factors whose binding is altered by the promoter insertion not determined\",\n        \"Net in vivo effect of the opposing regulatory changes (reduced transcription vs. reduced desensitization) on receptor density and signaling output unknown\",\n        \"No chromatin-level or endogenous gene expression data confirming the reporter findings\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of ADRA2B as a molecular target of the insecticide carbaryl, acting as an antagonist, established that ADRA2B blockade is sufficient to increase heart rate and impair larval behavior, providing in vivo evidence for ADRA2B's role in cardiovascular and neurobehavioral regulation.\",\n      \"evidence\": \"In silico target prediction with in vitro validation; pharmacological antagonism in zebrafish larvae using carbaryl and the prototypic antagonist yohimbine with heart rate and behavioral readouts\",\n      \"pmids\": [\"35248961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Zebrafish model; relevance to mammalian cardiovascular physiology not directly demonstrated\",\n        \"Selectivity of carbaryl for ADRA2B over other adrenergic receptor subtypes not fully resolved\",\n        \"Downstream intracellular signaling pathways mediating the heart rate and behavioral effects not characterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of transcription factors binding the ADRA2B promoter insertion site, the structural basis of impaired desensitization by the +901 Del variant, and the integrated physiological impact of the linked coding–promoter haplotype on adrenergic tone in mammalian systems remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or cryo-EM model of the α2B-adrenoceptor with or without the deletion\",\n        \"No mammalian knockout or knock-in studies dissecting the individual contributions of the promoter and coding variants\",\n        \"Downstream G-protein coupling specificity and arrestin recruitment kinetics for ADRA2B not characterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```"}