{"gene":"ADCY5","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2024,"finding":"Cryo-EM structures of AC5 in complex with Gβγ reveal that Gβγ binds to a coiled-coil domain linking the AC5 transmembrane region to its catalytic core and to the C1b regulatory hub; gain-of-function dyskinesia mutations in AC5 are located at the AC5-Gβγ interface and show reduced conditional activation by Gβγ, establishing a molecular mechanism for how these mutations cause disease.","method":"Cryo-electron microscopy, purified protein binding assays, cell-based cAMP assays, mutagenesis","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure plus orthogonal cell-based and biochemical validation with disease mutants","pmids":["38589608"],"is_preprint":false},{"year":2014,"finding":"Gain-of-function missense mutations in ADCY5 (p.R418W in C1 domain; p.A726T in first membrane-spanning domain) cause significantly increased β-adrenergic receptor agonist-stimulated intracellular cAMP accumulation, establishing that ADCY5 mutations cause familial dyskinesia through increased adenylyl cyclase activity.","method":"cAMP accumulation assay in transfected cells with wild-type and mutant ADCY5 constructs; whole exome sequencing","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 1/2 — direct in vitro functional assay of adenylyl cyclase activity with multiple mutants, replicated across families","pmids":["24700542"],"is_preprint":false},{"year":2019,"finding":"AC5 gain-of-function mutants (R418W, R418Q, A726T, M1029K) exhibit enhanced Gαs-mediated cAMP stimulation in membrane and cell-based assays, increased downstream gene transcription in neuronal models, and significantly reduced inhibition following D2 dopamine receptor (Gαi-coupled) activation; the P-site inhibitor SQ22536 preferentially inhibits overactive AC5 mutants.","method":"CRISPR-Cas9 knockout of endogenous adenylyl cyclases in HEK cells; membrane-based and cell-based cAMP assays; neuronal transcription reporter assays; pharmacological inhibition","journal":"Biochemical pharmacology","confidence":"High","confidence_rationale":"Tier 1/2 — multiple orthogonal assays in clean genetic background, multiple mutants characterized","pmids":["30772269"],"is_preprint":false},{"year":2014,"finding":"ADCY5 silencing in human islets impairs glucose-induced cAMP increases and blocks glucose metabolism toward ATP at >8 mmol/L glucose, and sharply inhibits calcium transient generation and functional connectivity between β-cells at all glucose concentrations; GLP-1-induced calcium rises are unaffected, demonstrating that ADCY5 specifically couples glucose (but not GLP-1) to insulin secretion.","method":"siRNA knockdown of ADCY5 in human islets; in situ imaging of cAMP and ATP probes; calcium imaging; functional connectivity analysis","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 — clean loss-of-function with multiple orthogonal readouts (cAMP, ATP, Ca2+, connectivity) in primary human tissue","pmids":["24740569"],"is_preprint":false},{"year":2010,"finding":"AKAP79/150 scaffolds AC5 (and AC6) to synaptic AMPA receptors; the N-terminal region of AC5 mediates binding to residues 77–108 of AKAP79; deletion of this AKAP79 region abolishes AC5-AKAP79 interaction in living cells; the AKAP79(77-153) polypeptide fragment uncouples AC5/6 from AKAP and prevents PKA-mediated inhibition of AC activity; loss of AKAP150 in mice reduces AMPA receptor-associated AC activity.","method":"Co-immunoprecipitation, pulldown, FRET (intensity- and lifetime-based) in living cells, AC activity assays in brain membranes from AKAP150-/- mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction mapping with FRET in live cells plus functional membrane assays in KO mice","pmids":["20231277"],"is_preprint":false},{"year":2006,"finding":"AC5 is an essential mediator of mu and delta (but not kappa) opioid receptor signaling in the striatum: AC5 knockout mice lack mu/delta opioid receptor agonist-induced suppression of adenylyl cyclase activity in striatum, and all major behavioral effects of morphine (locomotor activation, analgesia, tolerance, reward, physical dependence/withdrawal) are attenuated.","method":"AC5 knockout mice; biochemical adenylyl cyclase activity assay in striatal membranes; behavioral pharmacology with selective opioid receptor agonists","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with multiple orthogonal behavioral and biochemical readouts; isoform-specific pharmacological dissection","pmids":["16537460"],"is_preprint":false},{"year":2006,"finding":"Calcium inhibits renin exocytosis from juxtaglomerular cells by inhibiting AC5 and AC6: siRNA-mediated knockdown of AC5 and/or AC6 prevented calcium-dependent inhibition of intracellular cAMP levels and renin release; clamping cAMP with membrane-permeable analogs bypassed calcium suppression of renin secretion.","method":"siRNA knockdown in primary JG cells and As4.1 renin-producing cell line; cAMP measurements; renin secretion assays; isolated perfused mouse kidneys","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — siRNA knockdown in two cell systems plus ex vivo perfusion, with rescue experiments using membrane-permeable cAMP","pmids":["17068292"],"is_preprint":false},{"year":2002,"finding":"Both high and low affinity Ca2+ inhibition of AC5 are exerted through the Mg2+-binding sites in the catalytic domain: Mg2+ activation reduces absolute high-affinity inhibition without changing Ki, while decreasing the Ki for low-affinity inhibition; forskolin (acting by a different mechanism) does not modify Ca2+ inhibition; chimeric constructs confirmed that the catalytic domain alone is responsible for high-affinity Ca2+ inhibition.","method":"Site-directed mutagenesis of AC5, domain deletion mutants, AC5/AC2 chimeric constructs, in vitro adenylyl cyclase activity assays with Ca2+, Mg2+, Sr2+, Ba2+","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with mutagenesis and chimeric constructs probing catalytic mechanism","pmids":["12065575"],"is_preprint":false},{"year":2014,"finding":"AC5 overexpression in transgenic mice creates a proarrhythmic substrate by inducing SR Ca2+ overload, increasing SERCA2a levels, causing oxidative CaMKII activation, and hyperphosphorylation of ryanodine receptors at the CaMKII site, leading to spontaneous Ca2+ waves, afterdepolarizations, and triggered action potentials upon isoproterenol stimulation.","method":"AC5 transgenic mice; intracellular Ca2+ imaging (fluo-4 AM); action potential recordings; Western blotting for SERCA2a, phospho-RyR, oxidized CaMKII; ROS measurements; in vivo arrhythmia assays","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 2 — gain-of-function transgenic model with multiple orthogonal mechanistic readouts","pmids":["25485900"],"is_preprint":false},{"year":2012,"finding":"Dopamine D2 receptor-mediated heterologous sensitization of AC5 requires Gαs-AC5 interactions and proper signalosome assembly: neither Gαs palmitoylation nor Gαs-Gβγ interactions were required for sensitization, but βARKct-CD8 or dominant-negative Sar1(H79G) blocked sensitization, implicating vesicular trafficking in assembly of the AC5 signalosome.","method":"Expression of Gαs mutants in Gαs-deficient Gnas(E2-/E2-) cells; cAMP assays; dominant-negative trafficking inhibitors","journal":"Journal of signal transduction","confidence":"Medium","confidence_rationale":"Tier 2 — defined genetic/pharmacological epistasis in Gαs-null cells, single lab","pmids":["22523680"],"is_preprint":false},{"year":2019,"finding":"Bimolecular fluorescence complementation (BiFC) screening in striatal medium spiny neurons identified PP2A catalytic subunit (PPP2CB) and NAPA as novel AC5 interactors/modulators; PPP2CB knockdown reduced both acute and sensitized adenylyl cyclase activity, establishing PP2A as a persistent regulator of AC5 activity in D1 and D2 MSNs.","method":"BiFC protein-protein interaction screening, genetic knockdown, cAMP assays in D1/D2 MSNs from CAMPER mice","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2/3 — novel interaction screen with functional knockdown validation in relevant neuronal cell types, single lab","pmids":["31752385"],"is_preprint":false},{"year":2020,"finding":"AC5 is required for stress-induced suppression of GluA1 protein synthesis in Bergmann glial cells: deletion of adenylyl cyclase 5 prevented stress-induced GluA1 suppression, placing AC5 downstream of β-adrenergic receptor activation and upstream of CPEB3-dependent GluA1 mRNA regulation and glial process retraction.","method":"AC5 knockout mice; immunofluorescence and Western blotting for GluA1; electrophysiology; genetic epistasis with CPEB3 knockout and β-adrenergic blocker","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis in KO mice with cellular phenotype, single lab","pmids":["32229518"],"is_preprint":false},{"year":2022,"finding":"In zebrafish, Adcy3a and Adcy5 double mutants show defective melanosome dispersion (but not melanoblast differentiation); AC5-mediated cAMP-PKA signaling regulates melanosome dispersion by activating kinesin-1 and inhibiting cytoplasmic dynein-1; in adults, Adcy5 regulates Mitfa expression and melanin synthesis enzyme levels (Tyr, Dct, Trp1b), and loss of Adcy5 reduces pigmented melanocyte numbers.","method":"CRISPR/Cas9 knockout zebrafish; PKA activator rescue experiments; epistasis analysis of motor proteins","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO in zebrafish ortholog with mechanistic pathway placement and rescue, single lab","pmids":["36430661"],"is_preprint":false},{"year":2017,"finding":"A type 2 diabetes risk allele at rs11708067-A in an intronic enhancer of ADCY5 reduces H3K27ac marks, shows lower transcriptional activity in reporter assays in rodent β-cells, and increased nuclear protein binding; homozygous deletion of the orthologous enhancer in 832/13 cells reduces Adcy5 expression by 64% and insulin secretion by 39%.","method":"ChIP-seq, luciferase reporter assays, CRISPR enhancer deletion, insulin secretion assay","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 1/2 — multiple orthogonal methods including CRISPR deletion with functional readout, moderate evidence from two β-cell lines","pmids":["28684635"],"is_preprint":false},{"year":2021,"finding":"miR-18a-3p directly targets ADCY5 mRNA (confirmed by dual luciferase reporter and RNA pulldown); miR-18a-3p mimic inhibits osteogenic differentiation of hBMSCs, while ADCY5 overexpression promotes calcium deposition and osteoblast marker expression (OSX, ALP, RUNX2), and partially reverses miR-18a-3p-mediated inhibition.","method":"Dual luciferase reporter assay, RNA pulldown, overexpression and mimic transfection in hBMSCs, ALP activity and calcium deposition assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2/3 — direct molecular validation of miRNA targeting combined with functional rescue, single lab","pmids":["33684620"],"is_preprint":false},{"year":2023,"finding":"Caffeine, theophylline, and istradefylline all reduce cAMP production by ADCY5-overexpressing cells, with more pronounced effects on the gain-of-function R418W mutant than wild-type ADCY5, consistent with preferential inhibition of overactive AC5.","method":"cAMP measurement in ADCY5 wild-type and R418W mutant overexpressing cell lines treated with purine derivatives","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1/2 — direct in vitro cAMP assay comparing WT and GOF mutant, single lab","pmids":["36867608"],"is_preprint":false}],"current_model":"ADCY5 (adenylyl cyclase 5) is a membrane-anchored enzyme that converts ATP to cAMP, highly expressed in striatal medium spiny neurons and pancreatic β-cells; its catalytic activity is stimulated by Gαs, inhibited by Gαi-coupled receptors (including D2 dopamine and mu/delta opioid receptors) and by calcium acting on the Mg2+-binding sites of its catalytic domain, and is spatially organized by scaffolding proteins such as AKAP79/150; gain-of-function mutations at its Gβγ-binding interface (particularly R418W) increase Gαs-stimulated cAMP production while reducing inhibitory Gαi regulation, causing hyperkinetic movement disorders, whereas loss-of-function impairs glucose-stimulated cAMP and insulin secretion in β-cells and disrupts dopaminergic and opioid signaling in the striatum."},"narrative":{"teleology":[{"year":2002,"claim":"Defining how calcium inhibits AC5 resolved the long-standing question of which catalytic determinants confer calcium sensitivity: both high- and low-affinity Ca²⁺ inhibition operate through the Mg²⁺-binding sites in the catalytic domain itself, not through auxiliary domains.","evidence":"Site-directed mutagenesis, AC5/AC2 chimeric constructs, and in vitro enzyme assays with divalent cation titrations","pmids":["12065575"],"confidence":"High","gaps":["Structural basis of Ca²⁺ vs Mg²⁺ competition at the active site not resolved at atomic level","Whether Ca²⁺ inhibition is modulated by scaffolding context in vivo was untested"]},{"year":2006,"claim":"Knockout studies established AC5 as the specific adenylyl cyclase isoform coupling mu/delta opioid receptors and Gαi to cAMP suppression in the striatum, explaining isoform selectivity of opioid signaling and revealing AC5 as essential for morphine-induced behaviors including reward and dependence.","evidence":"AC5 knockout mice; striatal membrane adenylyl cyclase assays with selective opioid agonists; morphine behavioral pharmacology","pmids":["16537460"],"confidence":"High","gaps":["Whether AC5 loss is compensated by other AC isoforms over time was not assessed","Mechanism of kappa receptor sparing in AC5 KO striatum remained unexplained"]},{"year":2006,"claim":"Parallel work showed AC5 (together with AC6) mediates calcium-dependent suppression of cAMP and renin secretion in juxtaglomerular cells, extending AC5's role as a calcium-inhibited cyclase to a non-neuronal physiological context.","evidence":"siRNA knockdown of AC5/AC6 in primary juxtaglomerular cells and As4.1 line; cAMP rescue with membrane-permeable analogs; isolated perfused kidneys","pmids":["17068292"],"confidence":"High","gaps":["Relative contribution of AC5 vs AC6 to renin regulation in vivo not genetically separated"]},{"year":2010,"claim":"Mapping the AC5–AKAP79/150 interaction revealed how AC5 is scaffolded into signaling complexes: the AC5 N-terminus binds AKAP79 residues 77–108, and disruption of this scaffold uncouples PKA-mediated feedback inhibition of AC activity, establishing the spatial organization principle for AC5 signaling at synapses.","evidence":"Co-immunoprecipitation, FRET in live cells, AC activity assays in AKAP150-knockout mouse brain membranes","pmids":["20231277"],"confidence":"High","gaps":["Structural details of the AC5-AKAP interface at atomic resolution were lacking","Whether AKAP scaffolding modulates Gαi-mediated inhibition of AC5 was not tested"]},{"year":2012,"claim":"D2 receptor-mediated heterologous sensitization of AC5 was shown to require Gαs–AC5 interaction and vesicular trafficking for signalosome assembly, but not Gαs palmitoylation or Gβγ interaction, separating the trafficking requirements for sensitization from acute activation.","evidence":"Gαs mutant expression in Gαs-null cells; dominant-negative trafficking inhibitors; cAMP assays","pmids":["22523680"],"confidence":"Medium","gaps":["Vesicular trafficking mechanism delivering AC5 to the signalosome not molecularly defined","Single-lab finding without independent replication"]},{"year":2014,"claim":"Functional characterization of ADCY5 mutations (R418W, A726T) directly demonstrated that familial dyskinesia is caused by gain-of-function increases in Gαs-stimulated cAMP production, establishing the first genotype-to-mechanism link for ADCY5-related movement disorders.","evidence":"cAMP accumulation assays in transfected cells with wild-type and mutant ADCY5; whole-exome sequencing of affected families","pmids":["24700542"],"confidence":"High","gaps":["Why different mutations in distinct domains converge on gain-of-function was structurally unexplained","In vivo neuronal consequences of specific mutants were not assessed"]},{"year":2014,"claim":"In parallel, ADCY5 was identified as the specific adenylyl cyclase coupling glucose metabolism to cAMP, calcium transients, and β-cell functional connectivity in human islets—distinct from the GLP-1 pathway—directly linking the GWAS T2D risk locus to a defined secretory mechanism.","evidence":"siRNA knockdown in human islets; in situ cAMP, ATP, and calcium imaging; functional connectivity analysis","pmids":["24740569"],"confidence":"High","gaps":["Whether reduced ADCY5 expression in risk-allele carriers quantitatively accounts for diabetes susceptibility remained unresolved","Downstream effectors of AC5-generated cAMP in β-cells not fully delineated"]},{"year":2017,"claim":"The T2D risk variant rs11708067-A was shown to reduce enhancer activity at an intronic element, decreasing ADCY5 transcription and insulin secretion, providing a causal regulatory mechanism connecting non-coding genetic variation to AC5 expression and β-cell function.","evidence":"ChIP-seq for H3K27ac, luciferase reporters in β-cell lines, CRISPR enhancer deletion with insulin secretion readout","pmids":["28684635"],"confidence":"High","gaps":["Identity of transcription factors binding the risk vs protective allele not determined","Effect validated in rodent β-cell lines but not in human β-cells with endogenous genotype"]},{"year":2019,"claim":"Systematic characterization of four dyskinesia mutations in a clean genetic background showed that gain-of-function mutants share a dual defect—enhanced Gαs stimulation and reduced Gαi (D2 receptor) inhibition—and that P-site inhibitors preferentially suppress overactive mutants, opening a pharmacological strategy.","evidence":"CRISPR-Cas9 AC-null HEK cells reconstituted with WT or mutant AC5; membrane and whole-cell cAMP assays; neuronal transcription reporters","pmids":["30772269"],"confidence":"High","gaps":["Whether P-site inhibitors achieve selectivity in vivo without affecting other AC isoforms was untested","Circuit-level consequences of reduced Gαi sensitivity in MSNs were unexplored"]},{"year":2019,"claim":"A BiFC interaction screen in striatal MSNs identified PP2A catalytic subunit (PPP2CB) and NAPA as novel AC5 interactors, with PP2A knockdown reducing both acute and sensitized cAMP output, revealing phosphatase-mediated regulation of AC5.","evidence":"Bimolecular fluorescence complementation in D1/D2 MSNs from CAMPER mice; genetic knockdown; cAMP assays","pmids":["31752385"],"confidence":"Medium","gaps":["Direct physical binding of PP2A to AC5 not confirmed by reciprocal co-IP or structural data","Phosphorylation site(s) on AC5 regulated by PP2A not identified"]},{"year":2024,"claim":"Cryo-EM structures of AC5 in complex with Gβγ revealed that Gβγ binds a coiled-coil domain connecting the transmembrane region to the catalytic core and to the C1b regulatory hub, and that dyskinesia mutations (including R418W) map precisely to this interface, providing the atomic-level explanation for how they disrupt Gβγ-dependent conditional regulation and cause disease.","evidence":"Cryo-EM structures of AC5–Gβγ complex; mutagenesis; cell-based cAMP assays","pmids":["38589608"],"confidence":"High","gaps":["Full-length AC5 structure with Gαs and Gαi simultaneously bound not yet obtained","How the C1b hub integrates Gβγ, Ca²⁺, and PKA feedback structurally remains incomplete"]},{"year":null,"claim":"A unified structural model of AC5 incorporating simultaneous regulation by Gαs, Gαi, Gβγ, Ca²⁺, and AKAP scaffolding is still lacking, and no selective AC5 inhibitor has been validated in vivo for movement disorders or metabolic disease.","evidence":"","pmids":[],"confidence":"High","gaps":["No full-length AC5 structure with all regulators simultaneously resolved","No AC5-selective pharmacological tool validated in animal models of dyskinesia","Relative contributions of AC5 versus AC6 in shared tissues (heart, kidney) not genetically resolved in humans"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0009975","term_label":"cyclase activity","supporting_discovery_ids":[0,1,2,7]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,1,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,5,9]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2,5,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2]}],"complexes":["AKAP79/150-AC5-PKA signalosome"],"partners":["AKAP5","GNAS","GNAI1","GNB1","GNG2","PPP2CB","NAPA"],"other_free_text":[]},"mechanistic_narrative":"ADCY5 encodes adenylyl cyclase 5, a membrane-anchored enzyme that converts ATP to cAMP and serves as a central signal integrator in striatal neurons, pancreatic β-cells, juxtaglomerular cells, and cardiomyocytes. Its catalytic activity is stimulated by Gαs and conditionally modulated by Gβγ binding to a coiled-coil domain linking its transmembrane helices to the catalytic core, while calcium inhibits the enzyme through its Mg²⁺-binding catalytic sites; scaffolding by AKAP79/150 via the AC5 N-terminus organizes it into signalosomes with PKA and AMPA receptors [PMID:38589608, PMID:12065575, PMID:20231277]. In striatal medium spiny neurons, AC5 is the obligate effector downstream of mu/delta opioid and D2 dopamine Gαi-coupled receptors, and in pancreatic β-cells it specifically couples glucose metabolism to cAMP generation and insulin secretion, with a type 2 diabetes risk variant reducing ADCY5 expression from an intronic enhancer [PMID:16537460, PMID:24740569, PMID:28684635]. Gain-of-function mutations at the Gβγ-binding interface (notably R418W) increase Gαs-stimulated cAMP while impairing Gαi-mediated inhibition, causing familial dyskinesia with chorea [PMID:24700542, PMID:30772269]."},"prefetch_data":{"uniprot":{"accession":"O95622","full_name":"Adenylate cyclase type 5","aliases":["ATP pyrophosphate-lyase 5","Adenylate cyclase type V","Adenylyl cyclase 5","AC5"],"length_aa":1261,"mass_kda":138.9,"function":"Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling (PubMed:15385642, PubMed:24700542, PubMed:26206488). Mediates signaling downstream of ADRB1 (PubMed:24700542). Regulates the increase of free cytosolic Ca(2+) in response to increased blood glucose levels and contributes to the regulation of Ca(2+)-dependent insulin secretion (PubMed:24740569)","subcellular_location":"Cell membrane; Cell projection, cilium","url":"https://www.uniprot.org/uniprotkb/O95622/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADCY5","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADCY5","total_profiled":1310},"omim":[{"mim_id":"620638","title":"POTASSIUM CHANNEL TETRAMERIZATION DOMAIN-CONTAINING PROTEIN 4; KCTD4","url":"https://www.omim.org/entry/620638"},{"mim_id":"619651","title":"NEURODEVELOPMENTAL DISORDER WITH HYPERKINETIC MOVEMENTS AND DYSKINESIA; NEDHYD","url":"https://www.omim.org/entry/619651"},{"mim_id":"619647","title":"DYSKINESIA WITH OROFACIAL INVOLVEMENT, AUTOSOMAL RECESSIVE; DSKOR","url":"https://www.omim.org/entry/619647"},{"mim_id":"615192","title":"BIRTH WEIGHT QUANTITATIVE TRAIT LOCUS 4; BWQTL4","url":"https://www.omim.org/entry/615192"},{"mim_id":"613460","title":"FASTING PLASMA GLUCOSE LEVEL QUANTITATIVE TRAIT LOCUS 6; FGQTL6","url":"https://www.omim.org/entry/613460"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Nuclear bodies","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":74.2},{"tissue":"heart muscle","ntpm":99.3}],"url":"https://www.proteinatlas.org/search/ADCY5"},"hgnc":{"alias_symbol":["AC5"],"prev_symbol":[]},"alphafold":{"accession":"O95622","domains":[{"cath_id":"3.30.70.1230","chopping":"461-654","consensus_level":"high","plddt":85.4234,"start":461,"end":654},{"cath_id":"-","chopping":"764-856","consensus_level":"medium","plddt":87.6925,"start":764,"end":856},{"cath_id":"3.30.70.1230","chopping":"1049-1255","consensus_level":"high","plddt":86.1136,"start":1049,"end":1255}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95622","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95622-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95622-F1-predicted_aligned_error_v6.png","plddt_mean":73.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADCY5","jax_strain_url":"https://www.jax.org/strain/search?query=ADCY5"},"sequence":{"accession":"O95622","fasta_url":"https://rest.uniprot.org/uniprotkb/O95622.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95622/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95622"}},"corpus_meta":[{"pmid":"24740569","id":"PMC_24740569","title":"ADCY5 couples glucose to insulin secretion in human islets.","date":"2014","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/24740569","citation_count":122,"is_preprint":false},{"pmid":"27061943","id":"PMC_27061943","title":"Phenotypic insights into ADCY5-associated disease.","date":"2016","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/27061943","citation_count":103,"is_preprint":false},{"pmid":"26537056","id":"PMC_26537056","title":"ADCY5-related dyskinesia: Broader spectrum and genotype-phenotype correlations.","date":"2015","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/26537056","citation_count":101,"is_preprint":false},{"pmid":"24700542","id":"PMC_24700542","title":"Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia.","date":"2014","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24700542","citation_count":101,"is_preprint":false},{"pmid":"20231277","id":"PMC_20231277","title":"AKAP79 interacts with multiple adenylyl cyclase (AC) isoforms and scaffolds AC5 and -6 to alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20231277","citation_count":95,"is_preprint":false},{"pmid":"16537460","id":"PMC_16537460","title":"Adenylyl cyclase type 5 (AC5) is an essential mediator of morphine action.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16537460","citation_count":94,"is_preprint":false},{"pmid":"26010321","id":"PMC_26010321","title":"The AC5 protein encoded by Mungbean yellow mosaic India virus is a pathogenicity determinant that suppresses RNA silencing-based antiviral defenses.","date":"2015","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/26010321","citation_count":80,"is_preprint":false},{"pmid":"22080014","id":"PMC_22080014","title":"The effect of including Lactobacillus reuteri KUB-AC5 during post-hatch feeding on the growth and ileum microbiota of broiler chickens.","date":"2011","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/22080014","citation_count":72,"is_preprint":false},{"pmid":"26085604","id":"PMC_26085604","title":"ADCY5 mutations are another cause of benign hereditary chorea.","date":"2015","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/26085604","citation_count":70,"is_preprint":false},{"pmid":"28511835","id":"PMC_28511835","title":"ADCY5-related movement disorders: Frequency, disease course and phenotypic variability in a cohort of paediatric patients.","date":"2017","source":"Parkinsonism & related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/28511835","citation_count":64,"is_preprint":false},{"pmid":"17068292","id":"PMC_17068292","title":"The calcium paradoxon of renin release: calcium suppresses renin exocytosis by inhibition of calcium-dependent adenylate cyclases AC5 and AC6.","date":"2006","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/17068292","citation_count":64,"is_preprint":false},{"pmid":"25545163","id":"PMC_25545163","title":"A de novo ADCY5 mutation causes early-onset autosomal dominant chorea and dystonia.","date":"2014","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/25545163","citation_count":63,"is_preprint":false},{"pmid":"28684635","id":"PMC_28684635","title":"A Type 2 Diabetes-Associated Functional Regulatory Variant in a Pancreatic Islet Enhancer at the ADCY5 Locus.","date":"2017","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/28684635","citation_count":51,"is_preprint":false},{"pmid":"33934385","id":"PMC_33934385","title":"An Update on the Phenotype, Genotype and Neurobiology of ADCY5-Related Disease.","date":"2021","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/33934385","citation_count":44,"is_preprint":false},{"pmid":"35384065","id":"PMC_35384065","title":"Efficacy of Caffeine in ADCY5-Related Dyskinesia: A Retrospective Study.","date":"2022","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/35384065","citation_count":39,"is_preprint":false},{"pmid":"12065575","id":"PMC_12065575","title":"A critical interplay between Ca2+ inhibition and activation by Mg2+ of AC5 revealed by mutants and chimeric constructs.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12065575","citation_count":38,"is_preprint":false},{"pmid":"31538084","id":"PMC_31538084","title":"ADCY5-Related Dyskinesia: Improving Clinical Detection of an Evolving Disorder.","date":"2019","source":"Movement disorders clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/31538084","citation_count":38,"is_preprint":false},{"pmid":"30772269","id":"PMC_30772269","title":"Functional characterization of AC5 gain-of-function variants: Impact on the molecular basis of ADCY5-related dyskinesia.","date":"2019","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30772269","citation_count":37,"is_preprint":false},{"pmid":"24751013","id":"PMC_24751013","title":"Aluminum carboxymethyl cellulose-rice bran microcapsules: enhancing survival of Lactobacillus reuteri KUB-AC5.","date":"2012","source":"Carbohydrate polymers","url":"https://pubmed.ncbi.nlm.nih.gov/24751013","citation_count":37,"is_preprint":false},{"pmid":"27052971","id":"PMC_27052971","title":"Treatment of ADCY5-Associated Dystonia, Chorea, and Hyperkinetic Disorders With Deep Brain Stimulation: A Multicenter Case Series.","date":"2016","source":"Journal of child neurology","url":"https://pubmed.ncbi.nlm.nih.gov/27052971","citation_count":37,"is_preprint":false},{"pmid":"31752385","id":"PMC_31752385","title":"Identification of Novel Adenylyl Cyclase 5 (AC5) Signaling Networks in D1 and D2 Medium Spiny Neurons using Bimolecular Fluorescence Complementation Screening.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31752385","citation_count":35,"is_preprint":false},{"pmid":"30406695","id":"PMC_30406695","title":"Protective effect of Lactobacillus reuteri KUB-AC5 against Salmonella Enteritidis challenge in chickens.","date":"2018","source":"Beneficial microbes","url":"https://pubmed.ncbi.nlm.nih.gov/30406695","citation_count":33,"is_preprint":false},{"pmid":"30345538","id":"PMC_30345538","title":"PDE10A and ADCY5 mutations linked to molecular and microstructural basal ganglia pathology.","date":"2018","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/30345538","citation_count":30,"is_preprint":false},{"pmid":"28229249","id":"PMC_28229249","title":"ADCY5-related dyskinesia presenting as familial myoclonus-dystonia.","date":"2017","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/28229249","citation_count":30,"is_preprint":false},{"pmid":"21193983","id":"PMC_21193983","title":"Mice lacking adenylyl cyclase type 5 (AC5) show increased ethanol consumption and reduced ethanol sensitivity.","date":"2010","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/21193983","citation_count":26,"is_preprint":false},{"pmid":"30975617","id":"PMC_30975617","title":"Autosomal recessive ADCY5-Related dystonia and myoclonus: Expanding the genetic spectrum of ADCY5-Related movement disorders.","date":"2019","source":"Parkinsonism & related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/30975617","citation_count":22,"is_preprint":false},{"pmid":"32647899","id":"PMC_32647899","title":"Deep brain stimulation reduces (nocturnal) dyskinetic exacerbations in patients with ADCY5 mutation: a case series.","date":"2020","source":"Journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/32647899","citation_count":22,"is_preprint":false},{"pmid":"25485900","id":"PMC_25485900","title":"Overexpression of adenylyl cyclase type 5 (AC5) confers a proarrhythmic substrate to the heart.","date":"2014","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25485900","citation_count":21,"is_preprint":false},{"pmid":"37476318","id":"PMC_37476318","title":"Scoping Review on ADCY5-Related Movement Disorders.","date":"2023","source":"Movement disorders clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/37476318","citation_count":20,"is_preprint":false},{"pmid":"32949694","id":"PMC_32949694","title":"Polymorphic variants of bovine ADCY5 gene identified in GWAS analysis were significantly associated with ovarian morphological related traits.","date":"2020","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/32949694","citation_count":19,"is_preprint":false},{"pmid":"16269537","id":"PMC_16269537","title":"Probing the reorganization of the nicotinic acetylcholine receptor during desensitization by time-resolved covalent labeling using [3H]AC5, a photoactivatable agonist.","date":"2005","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/16269537","citation_count":18,"is_preprint":false},{"pmid":"38589608","id":"PMC_38589608","title":"Structure of adenylyl cyclase 5 in complex with Gβγ offers insights into ADCY5-related dyskinesia.","date":"2024","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/38589608","citation_count":17,"is_preprint":false},{"pmid":"32229518","id":"PMC_32229518","title":"Emotional Stress Induces Structural Plasticity in Bergmann Glial Cells via an AC5-CPEB3-GluA1 Pathway.","date":"2020","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/32229518","citation_count":16,"is_preprint":false},{"pmid":"24712513","id":"PMC_24712513","title":"Enhancement of Lactobacillus reuteri KUB-AC5 survival in broiler gastrointestinal tract by microencapsulation with alginate-chitosan semi-interpenetrating polymer networks.","date":"2014","source":"Journal of applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/24712513","citation_count":16,"is_preprint":false},{"pmid":"28442302","id":"PMC_28442302","title":"Facial twitches in ADCY5-associated disease - Myokymia or myoclonus? An electromyography study.","date":"2017","source":"Parkinsonism & related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/28442302","citation_count":14,"is_preprint":false},{"pmid":"29465345","id":"PMC_29465345","title":"The group I alphabaculovirus-specific protein, AC5, is a novel component of the occlusion body but is not associated with ODVs or the PIF complex.","date":"2018","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/29465345","citation_count":13,"is_preprint":false},{"pmid":"28873688","id":"PMC_28873688","title":"Combined effects of holy basil essential oil and inlet temperature on lipid peroxidation and survival of Lactobacillus reuteri KUB-AC5 during spray drying.","date":"2017","source":"Food research international (Ottawa, Ont.)","url":"https://pubmed.ncbi.nlm.nih.gov/28873688","citation_count":12,"is_preprint":false},{"pmid":"35205160","id":"PMC_35205160","title":"Probing Genome-Scale Model Reveals Metabolic Capability and Essential Nutrients for Growth of Probiotic Limosilactobacillus reuteri KUB-AC5.","date":"2022","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/35205160","citation_count":12,"is_preprint":false},{"pmid":"30172639","id":"PMC_30172639","title":"Depression and psychosis in ADCY5-related dyskinesia-part of the phenotypic spectrum?","date":"2018","source":"Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia","url":"https://pubmed.ncbi.nlm.nih.gov/30172639","citation_count":12,"is_preprint":false},{"pmid":"37120528","id":"PMC_37120528","title":"Development of high cell density Limosilactobacillus reuteri KUB-AC5 for cell factory using oxidative stress reduction approach.","date":"2023","source":"Microbial cell factories","url":"https://pubmed.ncbi.nlm.nih.gov/37120528","citation_count":11,"is_preprint":false},{"pmid":"34440550","id":"PMC_34440550","title":"ADCY5, CAPN10 and JAZF1 Gene Polymorphisms and Placental Expression in Women with Gestational Diabetes.","date":"2021","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34440550","citation_count":11,"is_preprint":false},{"pmid":"33919448","id":"PMC_33919448","title":"Effects of Whole-Body Adenylyl Cyclase 5 (Adcy5) Deficiency on Systemic Insulin Sensitivity and Adipose Tissue.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33919448","citation_count":9,"is_preprint":false},{"pmid":"36060769","id":"PMC_36060769","title":"AC5 protein encoded by squash leaf curl China virus is an RNA silencing suppressor and a virulence determinant.","date":"2022","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/36060769","citation_count":9,"is_preprint":false},{"pmid":"21712988","id":"PMC_21712988","title":"Absence of birth-weight lowering effect of ADCY5 and near CCNL, but association of impaired glucose-insulin homeostasis with ADCY5 in Asian Indians.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21712988","citation_count":9,"is_preprint":false},{"pmid":"36867608","id":"PMC_36867608","title":"Effects of theophylline on ADCY5 activation-From cellular studies to improved therapeutic options for ADCY5-related dyskinesia patients.","date":"2023","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/36867608","citation_count":8,"is_preprint":false},{"pmid":"32163478","id":"PMC_32163478","title":"Common genetic variants in ADCY5 and gestational glycemic traits.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/32163478","citation_count":8,"is_preprint":false},{"pmid":"22523680","id":"PMC_22523680","title":"Dopamine D(2) Receptor-Mediated Heterologous Sensitization of AC5 Requires Signalosome Assembly.","date":"2012","source":"Journal of signal transduction","url":"https://pubmed.ncbi.nlm.nih.gov/22523680","citation_count":8,"is_preprint":false},{"pmid":"33043083","id":"PMC_33043083","title":"Efficacy of Istradefylline for the Treatment of ADCY5-Related Disease.","date":"2020","source":"Movement disorders clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/33043083","citation_count":8,"is_preprint":false},{"pmid":"37906571","id":"PMC_37906571","title":"DNA methylation alterations of ADCY5, MICAL2, and PLEKHG2 during the developmental stage of cryptogenic hepatocellular carcinoma.","date":"2023","source":"Hepatology research : the official journal of the Japan Society of Hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/37906571","citation_count":7,"is_preprint":false},{"pmid":"35720494","id":"PMC_35720494","title":"Type 2 diabetes is more closely associated with risk of colorectal cancer based on elevated DNA methylation levels of ADCY5.","date":"2022","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/35720494","citation_count":7,"is_preprint":false},{"pmid":"32416839","id":"PMC_32416839","title":"Antimicrobial peptide presenting potential strain-specific real time polymerase chain reaction assay for detecting the probiotic Lactobacillus reuteri KUB-AC5 in chicken intestine.","date":"2019","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/32416839","citation_count":7,"is_preprint":false},{"pmid":"40079709","id":"PMC_40079709","title":"Treatment Efficacy of Theophylline in ADCY5-Related Dyskinesia: A Retrospective Case Series Study.","date":"2025","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/40079709","citation_count":6,"is_preprint":false},{"pmid":"33684620","id":"PMC_33684620","title":"By inhibiting ADCY5, miR-18a-3p promotes osteoporosis and possibly contributes to spinal fracture.","date":"2021","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/33684620","citation_count":6,"is_preprint":false},{"pmid":"39091675","id":"PMC_39091675","title":"Probiotic Limosilactobacillus reuteri KUB-AC5 decreases urothelial cell invasion and enhances macrophage killing of uropathogenic Escherichia coli in vitro study.","date":"2024","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/39091675","citation_count":6,"is_preprint":false},{"pmid":"33704598","id":"PMC_33704598","title":"Homozygous ADCY5 mutation causes early-onset movement disorder with severe intellectual disability.","date":"2021","source":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/33704598","citation_count":6,"is_preprint":false},{"pmid":"31970214","id":"PMC_31970214","title":"Hyperphosphorylated Tau, Increased Adenylate Cyclase 5 (ADCY5) Immunoreactivity, but No Neuronal Loss in ADCY5-Dyskinesia.","date":"2019","source":"Movement disorders clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/31970214","citation_count":6,"is_preprint":false},{"pmid":"36430661","id":"PMC_36430661","title":"Requirement of Zebrafish Adcy3a and Adcy5 in Melanosome Dispersion and Melanocyte Stripe Formation.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36430661","citation_count":4,"is_preprint":false},{"pmid":"34707932","id":"PMC_34707932","title":"Integrative growth physiology and transcriptome profiling of probiotic Limosilactobacillus reuteri KUB-AC5.","date":"2021","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/34707932","citation_count":3,"is_preprint":false},{"pmid":"38230756","id":"PMC_38230756","title":"ADCY5-related dyskinesia - case series with literature review.","date":"2024","source":"Neurologia i neurochirurgia polska","url":"https://pubmed.ncbi.nlm.nih.gov/38230756","citation_count":3,"is_preprint":false},{"pmid":"36539102","id":"PMC_36539102","title":"Early-life low-level lead exposure alters anxiety-like behavior, voluntary alcohol consumption and AC5 protein content in adult male and female C57BL/6 J mice.","date":"2022","source":"Neurotoxicology and teratology","url":"https://pubmed.ncbi.nlm.nih.gov/36539102","citation_count":3,"is_preprint":false},{"pmid":"39319137","id":"PMC_39319137","title":"ADCY5 act as a putative tumor suppressor in glioblastoma: An integrated analysis.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/39319137","citation_count":2,"is_preprint":false},{"pmid":"40004085","id":"PMC_40004085","title":"ADCY5 Gene Affects Seasonal Reproduction in Dairy Goats by Regulating Ovarian Granulosa Cells Steroid Hormone Synthesis.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40004085","citation_count":2,"is_preprint":false},{"pmid":"32627162","id":"PMC_32627162","title":"[ADCY5-associated dyskinesia in young children: a case report of a family and an updated review].","date":"2020","source":"Revista de neurologia","url":"https://pubmed.ncbi.nlm.nih.gov/32627162","citation_count":1,"is_preprint":false},{"pmid":"36112278","id":"PMC_36112278","title":"ADCY5 gene mutation: a case report.","date":"2022","source":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/36112278","citation_count":1,"is_preprint":false},{"pmid":"30754756","id":"PMC_30754756","title":"Accumulation of ζ-carotene in Chlamydomonas reinhardtii under control of the ac5 nuclear gene.","date":"1999","source":"Plant cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30754756","citation_count":1,"is_preprint":false},{"pmid":"26933606","id":"PMC_26933606","title":"ADCY5 Mutations and Benign Hereditary Chorea.","date":"2015","source":"Pediatric neurology briefs","url":"https://pubmed.ncbi.nlm.nih.gov/26933606","citation_count":1,"is_preprint":false},{"pmid":"40300124","id":"PMC_40300124","title":"Pearls & Oy-sters: ADCY5-Related Dyskinesia: From a Longstanding Misdiagnosis of Drug-Resistant Epilepsy.","date":"2025","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/40300124","citation_count":0,"is_preprint":false},{"pmid":"40908481","id":"PMC_40908481","title":"Artemisinin alleviates Parkinson's disease by targeting Adcy5-Gch1 axis to trigger a cascade generation of BH4 and dopamine in rats.","date":"2025","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/40908481","citation_count":0,"is_preprint":false},{"pmid":"41705003","id":"PMC_41705003","title":"Nocturnal Ballistic Bouts in ADCY5-Related Movement Disorder.","date":"2026","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/41705003","citation_count":0,"is_preprint":false},{"pmid":"39546632","id":"PMC_39546632","title":"A Single-Arm, Prospective Study of a Proprietary Synthetic Acellular Self-Assembling Peptide Wound Matrix, AC5® Advanced Wound System, for Treatment of Hard-to-Heal Wounds.","date":"2024","source":"Surgical technology international","url":"https://pubmed.ncbi.nlm.nih.gov/39546632","citation_count":0,"is_preprint":false},{"pmid":"38020658","id":"PMC_38020658","title":"Case report: Diagnosis of ADCY5-related dyskinesia explaining the entire phenotype in a patient with atypical citrullinemia type I.","date":"2023","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/38020658","citation_count":0,"is_preprint":false},{"pmid":"39919432","id":"PMC_39919432","title":"Generation of an induced pluripotent stem cell line (UCLi026-A) from a patient with ADCY5-related disease carrying the heterozygous variant c.1253G > A; (p. Arg418Gln).","date":"2025","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/39919432","citation_count":0,"is_preprint":false},{"pmid":"41782543","id":"PMC_41782543","title":"[Autosomal dominant dyskinesia associated with the ADCY5 gene].","date":"2026","source":"Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova","url":"https://pubmed.ncbi.nlm.nih.gov/41782543","citation_count":0,"is_preprint":false},{"pmid":"41799247","id":"PMC_41799247","title":"Mixed Movement Disorder Caused by ADCY5 Pathogenic Variant Successfully Treated With Caffeine: A Case From Ukraine.","date":"2026","source":"Case reports in neurological medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41799247","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.13.648593","title":"Developmental, neuroanatomical and cellular expression of genes causing dystonia","date":"2025-04-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.13.648593","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.19.660566","title":"Proteomic Characterization of Spodoptera frugiperda Granulovirus Occlusion Bodies","date":"2025-06-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.19.660566","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.23.24312408","title":"Treatment Efficacy of Theophylline in ADYC5 Dyskinesia: A Retrospective Case Series Study","date":"2024-08-23","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.23.24312408","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.18.619152","title":"Rapid Hippocampal Synaptic Potentiation Induced by Ketamine Metabolite (<i>2R</i>,<i>6R</i>)-Hydroxynorketamine Persistently Primes Synaptic Plasticity","date":"2024-10-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.18.619152","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.02.24316741","title":"Genetic Diversity and Expanded Phenotypes in Dystonia: Insights from Large-Scale Exome Sequencing","date":"2024-12-05","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.02.24316741","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.05.10.593618","title":"Personalized transcriptome signatures in a cardiomyopathy stem cell biobank","date":"2024-05-14","source":"bioRxiv","url":"https://doi.org/10.1101/2024.05.10.593618","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":40695,"output_tokens":4165,"usd":0.09228},"stage2":{"model":"claude-opus-4-6","input_tokens":7695,"output_tokens":3158,"usd":0.176138},"total_usd":0.268418,"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\": 2024,\n      \"finding\": \"Cryo-EM structures of AC5 in complex with Gβγ reveal that Gβγ binds to a coiled-coil domain linking the AC5 transmembrane region to its catalytic core and to the C1b regulatory hub; gain-of-function dyskinesia mutations in AC5 are located at the AC5-Gβγ interface and show reduced conditional activation by Gβγ, establishing a molecular mechanism for how these mutations cause disease.\",\n      \"method\": \"Cryo-electron microscopy, purified protein binding assays, cell-based cAMP assays, mutagenesis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure plus orthogonal cell-based and biochemical validation with disease mutants\",\n      \"pmids\": [\"38589608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Gain-of-function missense mutations in ADCY5 (p.R418W in C1 domain; p.A726T in first membrane-spanning domain) cause significantly increased β-adrenergic receptor agonist-stimulated intracellular cAMP accumulation, establishing that ADCY5 mutations cause familial dyskinesia through increased adenylyl cyclase activity.\",\n      \"method\": \"cAMP accumulation assay in transfected cells with wild-type and mutant ADCY5 constructs; whole exome sequencing\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — direct in vitro functional assay of adenylyl cyclase activity with multiple mutants, replicated across families\",\n      \"pmids\": [\"24700542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AC5 gain-of-function mutants (R418W, R418Q, A726T, M1029K) exhibit enhanced Gαs-mediated cAMP stimulation in membrane and cell-based assays, increased downstream gene transcription in neuronal models, and significantly reduced inhibition following D2 dopamine receptor (Gαi-coupled) activation; the P-site inhibitor SQ22536 preferentially inhibits overactive AC5 mutants.\",\n      \"method\": \"CRISPR-Cas9 knockout of endogenous adenylyl cyclases in HEK cells; membrane-based and cell-based cAMP assays; neuronal transcription reporter assays; pharmacological inhibition\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — multiple orthogonal assays in clean genetic background, multiple mutants characterized\",\n      \"pmids\": [\"30772269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ADCY5 silencing in human islets impairs glucose-induced cAMP increases and blocks glucose metabolism toward ATP at >8 mmol/L glucose, and sharply inhibits calcium transient generation and functional connectivity between β-cells at all glucose concentrations; GLP-1-induced calcium rises are unaffected, demonstrating that ADCY5 specifically couples glucose (but not GLP-1) to insulin secretion.\",\n      \"method\": \"siRNA knockdown of ADCY5 in human islets; in situ imaging of cAMP and ATP probes; calcium imaging; functional connectivity analysis\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with multiple orthogonal readouts (cAMP, ATP, Ca2+, connectivity) in primary human tissue\",\n      \"pmids\": [\"24740569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AKAP79/150 scaffolds AC5 (and AC6) to synaptic AMPA receptors; the N-terminal region of AC5 mediates binding to residues 77–108 of AKAP79; deletion of this AKAP79 region abolishes AC5-AKAP79 interaction in living cells; the AKAP79(77-153) polypeptide fragment uncouples AC5/6 from AKAP and prevents PKA-mediated inhibition of AC activity; loss of AKAP150 in mice reduces AMPA receptor-associated AC activity.\",\n      \"method\": \"Co-immunoprecipitation, pulldown, FRET (intensity- and lifetime-based) in living cells, AC activity assays in brain membranes from AKAP150-/- mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction mapping with FRET in live cells plus functional membrane assays in KO mice\",\n      \"pmids\": [\"20231277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"AC5 is an essential mediator of mu and delta (but not kappa) opioid receptor signaling in the striatum: AC5 knockout mice lack mu/delta opioid receptor agonist-induced suppression of adenylyl cyclase activity in striatum, and all major behavioral effects of morphine (locomotor activation, analgesia, tolerance, reward, physical dependence/withdrawal) are attenuated.\",\n      \"method\": \"AC5 knockout mice; biochemical adenylyl cyclase activity assay in striatal membranes; behavioral pharmacology with selective opioid receptor agonists\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple orthogonal behavioral and biochemical readouts; isoform-specific pharmacological dissection\",\n      \"pmids\": [\"16537460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Calcium inhibits renin exocytosis from juxtaglomerular cells by inhibiting AC5 and AC6: siRNA-mediated knockdown of AC5 and/or AC6 prevented calcium-dependent inhibition of intracellular cAMP levels and renin release; clamping cAMP with membrane-permeable analogs bypassed calcium suppression of renin secretion.\",\n      \"method\": \"siRNA knockdown in primary JG cells and As4.1 renin-producing cell line; cAMP measurements; renin secretion assays; isolated perfused mouse kidneys\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — siRNA knockdown in two cell systems plus ex vivo perfusion, with rescue experiments using membrane-permeable cAMP\",\n      \"pmids\": [\"17068292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Both high and low affinity Ca2+ inhibition of AC5 are exerted through the Mg2+-binding sites in the catalytic domain: Mg2+ activation reduces absolute high-affinity inhibition without changing Ki, while decreasing the Ki for low-affinity inhibition; forskolin (acting by a different mechanism) does not modify Ca2+ inhibition; chimeric constructs confirmed that the catalytic domain alone is responsible for high-affinity Ca2+ inhibition.\",\n      \"method\": \"Site-directed mutagenesis of AC5, domain deletion mutants, AC5/AC2 chimeric constructs, in vitro adenylyl cyclase activity assays with Ca2+, Mg2+, Sr2+, Ba2+\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with mutagenesis and chimeric constructs probing catalytic mechanism\",\n      \"pmids\": [\"12065575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AC5 overexpression in transgenic mice creates a proarrhythmic substrate by inducing SR Ca2+ overload, increasing SERCA2a levels, causing oxidative CaMKII activation, and hyperphosphorylation of ryanodine receptors at the CaMKII site, leading to spontaneous Ca2+ waves, afterdepolarizations, and triggered action potentials upon isoproterenol stimulation.\",\n      \"method\": \"AC5 transgenic mice; intracellular Ca2+ imaging (fluo-4 AM); action potential recordings; Western blotting for SERCA2a, phospho-RyR, oxidized CaMKII; ROS measurements; in vivo arrhythmia assays\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function transgenic model with multiple orthogonal mechanistic readouts\",\n      \"pmids\": [\"25485900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Dopamine D2 receptor-mediated heterologous sensitization of AC5 requires Gαs-AC5 interactions and proper signalosome assembly: neither Gαs palmitoylation nor Gαs-Gβγ interactions were required for sensitization, but βARKct-CD8 or dominant-negative Sar1(H79G) blocked sensitization, implicating vesicular trafficking in assembly of the AC5 signalosome.\",\n      \"method\": \"Expression of Gαs mutants in Gαs-deficient Gnas(E2-/E2-) cells; cAMP assays; dominant-negative trafficking inhibitors\",\n      \"journal\": \"Journal of signal transduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined genetic/pharmacological epistasis in Gαs-null cells, single lab\",\n      \"pmids\": [\"22523680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Bimolecular fluorescence complementation (BiFC) screening in striatal medium spiny neurons identified PP2A catalytic subunit (PPP2CB) and NAPA as novel AC5 interactors/modulators; PPP2CB knockdown reduced both acute and sensitized adenylyl cyclase activity, establishing PP2A as a persistent regulator of AC5 activity in D1 and D2 MSNs.\",\n      \"method\": \"BiFC protein-protein interaction screening, genetic knockdown, cAMP assays in D1/D2 MSNs from CAMPER mice\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — novel interaction screen with functional knockdown validation in relevant neuronal cell types, single lab\",\n      \"pmids\": [\"31752385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AC5 is required for stress-induced suppression of GluA1 protein synthesis in Bergmann glial cells: deletion of adenylyl cyclase 5 prevented stress-induced GluA1 suppression, placing AC5 downstream of β-adrenergic receptor activation and upstream of CPEB3-dependent GluA1 mRNA regulation and glial process retraction.\",\n      \"method\": \"AC5 knockout mice; immunofluorescence and Western blotting for GluA1; electrophysiology; genetic epistasis with CPEB3 knockout and β-adrenergic blocker\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in KO mice with cellular phenotype, single lab\",\n      \"pmids\": [\"32229518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In zebrafish, Adcy3a and Adcy5 double mutants show defective melanosome dispersion (but not melanoblast differentiation); AC5-mediated cAMP-PKA signaling regulates melanosome dispersion by activating kinesin-1 and inhibiting cytoplasmic dynein-1; in adults, Adcy5 regulates Mitfa expression and melanin synthesis enzyme levels (Tyr, Dct, Trp1b), and loss of Adcy5 reduces pigmented melanocyte numbers.\",\n      \"method\": \"CRISPR/Cas9 knockout zebrafish; PKA activator rescue experiments; epistasis analysis of motor proteins\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO in zebrafish ortholog with mechanistic pathway placement and rescue, single lab\",\n      \"pmids\": [\"36430661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A type 2 diabetes risk allele at rs11708067-A in an intronic enhancer of ADCY5 reduces H3K27ac marks, shows lower transcriptional activity in reporter assays in rodent β-cells, and increased nuclear protein binding; homozygous deletion of the orthologous enhancer in 832/13 cells reduces Adcy5 expression by 64% and insulin secretion by 39%.\",\n      \"method\": \"ChIP-seq, luciferase reporter assays, CRISPR enhancer deletion, insulin secretion assay\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — multiple orthogonal methods including CRISPR deletion with functional readout, moderate evidence from two β-cell lines\",\n      \"pmids\": [\"28684635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-18a-3p directly targets ADCY5 mRNA (confirmed by dual luciferase reporter and RNA pulldown); miR-18a-3p mimic inhibits osteogenic differentiation of hBMSCs, while ADCY5 overexpression promotes calcium deposition and osteoblast marker expression (OSX, ALP, RUNX2), and partially reverses miR-18a-3p-mediated inhibition.\",\n      \"method\": \"Dual luciferase reporter assay, RNA pulldown, overexpression and mimic transfection in hBMSCs, ALP activity and calcium deposition assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — direct molecular validation of miRNA targeting combined with functional rescue, single lab\",\n      \"pmids\": [\"33684620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Caffeine, theophylline, and istradefylline all reduce cAMP production by ADCY5-overexpressing cells, with more pronounced effects on the gain-of-function R418W mutant than wild-type ADCY5, consistent with preferential inhibition of overactive AC5.\",\n      \"method\": \"cAMP measurement in ADCY5 wild-type and R418W mutant overexpressing cell lines treated with purine derivatives\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/2 — direct in vitro cAMP assay comparing WT and GOF mutant, single lab\",\n      \"pmids\": [\"36867608\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADCY5 (adenylyl cyclase 5) is a membrane-anchored enzyme that converts ATP to cAMP, highly expressed in striatal medium spiny neurons and pancreatic β-cells; its catalytic activity is stimulated by Gαs, inhibited by Gαi-coupled receptors (including D2 dopamine and mu/delta opioid receptors) and by calcium acting on the Mg2+-binding sites of its catalytic domain, and is spatially organized by scaffolding proteins such as AKAP79/150; gain-of-function mutations at its Gβγ-binding interface (particularly R418W) increase Gαs-stimulated cAMP production while reducing inhibitory Gαi regulation, causing hyperkinetic movement disorders, whereas loss-of-function impairs glucose-stimulated cAMP and insulin secretion in β-cells and disrupts dopaminergic and opioid signaling in the striatum.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ADCY5 encodes adenylyl cyclase 5, a membrane-anchored enzyme that converts ATP to cAMP and serves as a central signal integrator in striatal neurons, pancreatic β-cells, juxtaglomerular cells, and cardiomyocytes. Its catalytic activity is stimulated by Gαs and conditionally modulated by Gβγ binding to a coiled-coil domain linking its transmembrane helices to the catalytic core, while calcium inhibits the enzyme through its Mg²⁺-binding catalytic sites; scaffolding by AKAP79/150 via the AC5 N-terminus organizes it into signalosomes with PKA and AMPA receptors [PMID:38589608, PMID:12065575, PMID:20231277]. In striatal medium spiny neurons, AC5 is the obligate effector downstream of mu/delta opioid and D2 dopamine Gαi-coupled receptors, and in pancreatic β-cells it specifically couples glucose metabolism to cAMP generation and insulin secretion, with a type 2 diabetes risk variant reducing ADCY5 expression from an intronic enhancer [PMID:16537460, PMID:24740569, PMID:28684635]. Gain-of-function mutations at the Gβγ-binding interface (notably R418W) increase Gαs-stimulated cAMP while impairing Gαi-mediated inhibition, causing familial dyskinesia with chorea [PMID:24700542, PMID:30772269].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Defining how calcium inhibits AC5 resolved the long-standing question of which catalytic determinants confer calcium sensitivity: both high- and low-affinity Ca²⁺ inhibition operate through the Mg²⁺-binding sites in the catalytic domain itself, not through auxiliary domains.\",\n      \"evidence\": \"Site-directed mutagenesis, AC5/AC2 chimeric constructs, and in vitro enzyme assays with divalent cation titrations\",\n      \"pmids\": [\"12065575\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Ca²⁺ vs Mg²⁺ competition at the active site not resolved at atomic level\", \"Whether Ca²⁺ inhibition is modulated by scaffolding context in vivo was untested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Knockout studies established AC5 as the specific adenylyl cyclase isoform coupling mu/delta opioid receptors and Gαi to cAMP suppression in the striatum, explaining isoform selectivity of opioid signaling and revealing AC5 as essential for morphine-induced behaviors including reward and dependence.\",\n      \"evidence\": \"AC5 knockout mice; striatal membrane adenylyl cyclase assays with selective opioid agonists; morphine behavioral pharmacology\",\n      \"pmids\": [\"16537460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AC5 loss is compensated by other AC isoforms over time was not assessed\", \"Mechanism of kappa receptor sparing in AC5 KO striatum remained unexplained\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Parallel work showed AC5 (together with AC6) mediates calcium-dependent suppression of cAMP and renin secretion in juxtaglomerular cells, extending AC5's role as a calcium-inhibited cyclase to a non-neuronal physiological context.\",\n      \"evidence\": \"siRNA knockdown of AC5/AC6 in primary juxtaglomerular cells and As4.1 line; cAMP rescue with membrane-permeable analogs; isolated perfused kidneys\",\n      \"pmids\": [\"17068292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of AC5 vs AC6 to renin regulation in vivo not genetically separated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapping the AC5–AKAP79/150 interaction revealed how AC5 is scaffolded into signaling complexes: the AC5 N-terminus binds AKAP79 residues 77–108, and disruption of this scaffold uncouples PKA-mediated feedback inhibition of AC activity, establishing the spatial organization principle for AC5 signaling at synapses.\",\n      \"evidence\": \"Co-immunoprecipitation, FRET in live cells, AC activity assays in AKAP150-knockout mouse brain membranes\",\n      \"pmids\": [\"20231277\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural details of the AC5-AKAP interface at atomic resolution were lacking\", \"Whether AKAP scaffolding modulates Gαi-mediated inhibition of AC5 was not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"D2 receptor-mediated heterologous sensitization of AC5 was shown to require Gαs–AC5 interaction and vesicular trafficking for signalosome assembly, but not Gαs palmitoylation or Gβγ interaction, separating the trafficking requirements for sensitization from acute activation.\",\n      \"evidence\": \"Gαs mutant expression in Gαs-null cells; dominant-negative trafficking inhibitors; cAMP assays\",\n      \"pmids\": [\"22523680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Vesicular trafficking mechanism delivering AC5 to the signalosome not molecularly defined\", \"Single-lab finding without independent replication\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Functional characterization of ADCY5 mutations (R418W, A726T) directly demonstrated that familial dyskinesia is caused by gain-of-function increases in Gαs-stimulated cAMP production, establishing the first genotype-to-mechanism link for ADCY5-related movement disorders.\",\n      \"evidence\": \"cAMP accumulation assays in transfected cells with wild-type and mutant ADCY5; whole-exome sequencing of affected families\",\n      \"pmids\": [\"24700542\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why different mutations in distinct domains converge on gain-of-function was structurally unexplained\", \"In vivo neuronal consequences of specific mutants were not assessed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"In parallel, ADCY5 was identified as the specific adenylyl cyclase coupling glucose metabolism to cAMP, calcium transients, and β-cell functional connectivity in human islets—distinct from the GLP-1 pathway—directly linking the GWAS T2D risk locus to a defined secretory mechanism.\",\n      \"evidence\": \"siRNA knockdown in human islets; in situ cAMP, ATP, and calcium imaging; functional connectivity analysis\",\n      \"pmids\": [\"24740569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether reduced ADCY5 expression in risk-allele carriers quantitatively accounts for diabetes susceptibility remained unresolved\", \"Downstream effectors of AC5-generated cAMP in β-cells not fully delineated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The T2D risk variant rs11708067-A was shown to reduce enhancer activity at an intronic element, decreasing ADCY5 transcription and insulin secretion, providing a causal regulatory mechanism connecting non-coding genetic variation to AC5 expression and β-cell function.\",\n      \"evidence\": \"ChIP-seq for H3K27ac, luciferase reporters in β-cell lines, CRISPR enhancer deletion with insulin secretion readout\",\n      \"pmids\": [\"28684635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of transcription factors binding the risk vs protective allele not determined\", \"Effect validated in rodent β-cell lines but not in human β-cells with endogenous genotype\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Systematic characterization of four dyskinesia mutations in a clean genetic background showed that gain-of-function mutants share a dual defect—enhanced Gαs stimulation and reduced Gαi (D2 receptor) inhibition—and that P-site inhibitors preferentially suppress overactive mutants, opening a pharmacological strategy.\",\n      \"evidence\": \"CRISPR-Cas9 AC-null HEK cells reconstituted with WT or mutant AC5; membrane and whole-cell cAMP assays; neuronal transcription reporters\",\n      \"pmids\": [\"30772269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether P-site inhibitors achieve selectivity in vivo without affecting other AC isoforms was untested\", \"Circuit-level consequences of reduced Gαi sensitivity in MSNs were unexplored\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A BiFC interaction screen in striatal MSNs identified PP2A catalytic subunit (PPP2CB) and NAPA as novel AC5 interactors, with PP2A knockdown reducing both acute and sensitized cAMP output, revealing phosphatase-mediated regulation of AC5.\",\n      \"evidence\": \"Bimolecular fluorescence complementation in D1/D2 MSNs from CAMPER mice; genetic knockdown; cAMP assays\",\n      \"pmids\": [\"31752385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical binding of PP2A to AC5 not confirmed by reciprocal co-IP or structural data\", \"Phosphorylation site(s) on AC5 regulated by PP2A not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cryo-EM structures of AC5 in complex with Gβγ revealed that Gβγ binds a coiled-coil domain connecting the transmembrane region to the catalytic core and to the C1b regulatory hub, and that dyskinesia mutations (including R418W) map precisely to this interface, providing the atomic-level explanation for how they disrupt Gβγ-dependent conditional regulation and cause disease.\",\n      \"evidence\": \"Cryo-EM structures of AC5–Gβγ complex; mutagenesis; cell-based cAMP assays\",\n      \"pmids\": [\"38589608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length AC5 structure with Gαs and Gαi simultaneously bound not yet obtained\", \"How the C1b hub integrates Gβγ, Ca²⁺, and PKA feedback structurally remains incomplete\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified structural model of AC5 incorporating simultaneous regulation by Gαs, Gαi, Gβγ, Ca²⁺, and AKAP scaffolding is still lacking, and no selective AC5 inhibitor has been validated in vivo for movement disorders or metabolic disease.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length AC5 structure with all regulators simultaneously resolved\", \"No AC5-selective pharmacological tool validated in animal models of dyskinesia\", \"Relative contributions of AC5 versus AC6 in shared tissues (heart, kidney) not genetically resolved in humans\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0009975\", \"supporting_discovery_ids\": [0, 1, 2, 7]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 1, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0007165\", \"supporting_discovery_ids\": [0, 2, 5, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 5, 9]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 5, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\n      \"AKAP79/150-AC5-PKA signalosome\"\n    ],\n    \"partners\": [\n      \"AKAP5\",\n      \"GNAS\",\n      \"GNAI1\",\n      \"GNB1\",\n      \"GNG2\",\n      \"PPP2CB\",\n      \"NAPA\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}