{"gene":"UNC80","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2008,"finding":"UNC-80 is required for proper localization of NCA-1 and NCA-2 ion channel subunits in C. elegans neurons; loss of unc-80 mislocalizes these channels, and unc-80 mutants suppress locomotory, vesicle depletion, and electrophysiological defects of synaptojanin mutants, placing UNC-80 downstream of PIP2 accumulation in synaptic vesicle recycling.","method":"Genetic suppressor screen in C. elegans; immunolocalization of NCA-1/NCA-2; electrophysiology","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with clean loss-of-function, localization experiments, and electrophysiology in single lab","pmids":["17825559"],"is_preprint":false},{"year":2008,"finding":"In C. elegans, UNC-80 is a novel conserved neuronal protein enriched at nonsynaptic regions that is required for NCA-1 localization along axons and for the propagation of depolarization signals from cell bodies to synapses; UNC-80 function and localization depend on UNC-79.","method":"Loss-of-function genetics in C. elegans; in vivo calcium imaging; immunolocalization","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (genetics, calcium imaging, localization) in single lab","pmids":["18336069"],"is_preprint":false},{"year":2008,"finding":"UNC-80 forms a complex with the NALCN cation channel and is required for activation of NALCN by substance P and neurotensin in mouse hippocampal and VTA neurons; this activation occurs through a G-protein-independent mechanism dependent on Src family kinases.","method":"Whole-cell patch-clamp electrophysiology in mouse neurons; co-immunoprecipitation; neuropeptide stimulation assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, electrophysiology with defined pharmacology, replicated across two neuron types, published in high-impact journal","pmids":["19092807"],"is_preprint":false},{"year":2009,"finding":"UNC80 physically binds Src kinases and recruits Src into the NALCN channel complex, functioning as a scaffold for Src kinases to enable G-protein-independent activation of NALCN by substance P.","method":"Co-immunoprecipitation; pulldown assays","journal":"Channels (Austin, Tex.)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP evidence from single lab, consistent with prior electrophysiology data, but single method for the specific Src binding claim","pmids":["19535918"],"is_preprint":false},{"year":2010,"finding":"UNC80 bridges NALCN to UNC79 within the same channel complex, and this UNC79-UNC80-NALCN complex is required for coupling extracellular Ca2+ sensing (via a Ca2+-sensing GPCR and G-protein activation) to activation of a Na+-leak current in hippocampal neurons; loss of unc79 or nalcn abolishes the [Ca2+]e-dependent I(L-Na).","method":"Whole-cell patch-clamp in cultured hippocampal neurons from knockout mice; co-immunoprecipitation; pharmacological dissection of G-protein pathway","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse electrophysiology, Co-IP, pharmacological rescue, multiple orthogonal methods in single well-controlled study","pmids":["21040849"],"is_preprint":false},{"year":2013,"finding":"In Drosophila, UNC80 (CG18437) forms a complex with NA (NALCN ortholog) and UNC79 in brain neurons; loss of unc80 phenocopies na mutant circadian locomotor rhythm defects; UNC79, UNC80, and NA show interdependent post-transcriptional regulation such that loss of any one reduces protein (but not transcript) levels of all three; UNC80 requirement for rhythmicity cannot be bypassed by increased NA expression nor substituted by UNC79.","method":"Immunoprecipitation from Drosophila brain; tissue-specific RNAi; genetic rescue experiments; western blotting and RT-PCR","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, genetic epistasis, RNAi rescue, protein/transcript analysis with multiple orthogonal methods in single study","pmids":["24223770"],"is_preprint":false},{"year":2015,"finding":"A missense mutation (p.Pro1700Ser) in UNC80 markedly decreases NALCN channel currents in HEK293T cells, demonstrating that UNC80 is required for NALCN channel function.","method":"Patch-clamp electrophysiology in transfected HEK293T cells expressing mutant UNC80","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional electrophysiology with disease-associated mutant, single lab, single mutation tested","pmids":["26708751"],"is_preprint":false},{"year":2020,"finding":"UNC80 and UNC79 are bona fide subunits of the NALCN complex; the C-terminus of UNC80 contains a domain that interacts with UNC79 and is required to overcome a soma-retention signal to achieve dendritic localization of the complex; UNC80 lacking this C-terminal domain still supports whole-cell NALCN currents but loses dendritic localization, implicating the UNC79-UNC80 interaction in regulation of dendritic membrane potential; UNC80 knockout mice are neonatal lethal.","method":"Co-immunoprecipitation; domain deletion analysis; live imaging of dendritic localization; whole-cell patch-clamp electrophysiology; UNC80 knockout mice","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mutagenesis, localization imaging with functional electrophysiology, knockout lethality, multiple orthogonal methods in single study","pmids":["32620897"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structure of the mammalian NALCN-FAM155A-UNC79-UNC80 quaternary complex reveals that UNC79 and UNC80 form a large pillar-shaped heterodimer tethered to the intracellular side of NALCN through tripartite interactions with cytoplasmic loops of NALCN; two of these interactions are essential for proper cell surface localization of NALCN; the third interaction relieves NALCN self-inhibition by pulling the auto-inhibitory CTD Interacting Helix (CIH) out of its binding site.","method":"Cryo-EM structure determination; functional validation of localization and channel activity by mutagenesis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with mutagenesis-based functional validation of multiple interaction sites and mechanism","pmids":["35550517"],"is_preprint":false},{"year":2024,"finding":"UNC80 undergoes A-to-I RNA editing at a codon-altering site in the brain in an ADAR2-dependent manner; gain-of-editing knock-in mice (Unc80G/G) show heightened basal neuronal activity in olfactory regions and increased glutamate levels in the olfactory bulb compared to loss-of-editing mice (Unc80S/S), indicating the editing event modulates neuronal excitability and neurotransmitter dynamics.","method":"CRISPR/Cas9 knock-in mouse models; in vivo neuronal activity measurements; glutamate level quantification; behavioral olfaction assays; transcriptomic analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR knock-in models with multiple physiological readouts, single lab, novel finding not yet replicated","pmids":["38892173"],"is_preprint":false}],"current_model":"UNC80 is a large cytoplasmic auxiliary subunit of the NALCN sodium-leak channel complex that physically bridges NALCN to UNC79 via its C-terminal domain; the cryo-EM structure shows UNC79-UNC80 form a pillar-shaped heterodimer docked to NALCN's intracellular loops through tripartite contacts that promote NALCN cell-surface localization and relieve NALCN auto-inhibition, while UNC80 also scaffolds Src kinases into the complex to enable G-protein-independent, substance-P-receptor-driven channel activation, and its C-terminus is required for dendritic (rather than somatic) localization of the complex to regulate dendritic membrane potential."},"narrative":{"mechanistic_narrative":"UNC80 is a large cytoplasmic auxiliary subunit of the NALCN sodium-leak channel complex that scaffolds the channel and controls its localization and gating in neurons [PMID:19092807, PMID:32620897]. It bridges NALCN to UNC79, forming a pillar-shaped UNC79-UNC80 heterodimer that docks onto the intracellular loops of NALCN through tripartite contacts; two of these contacts drive NALCN cell-surface localization while the third relieves NALCN auto-inhibition by extracting the channel's auto-inhibitory CTD-interacting helix from its binding site [PMID:35550517]. UNC80, UNC79, and NALCN are mutually interdependent for stability, with loss of any one reducing protein levels of all three [PMID:24223770], and in C. elegans UNC-80 is required for axonal localization of the channel and for propagation of depolarization from cell body to synapse [PMID:17825559, PMID:18336069]. A C-terminal domain of UNC80 mediates the UNC79 interaction and overcomes a soma-retention signal to achieve dendritic localization of the complex, thereby regulating dendritic membrane potential [PMID:32620897]. Beyond its structural role, UNC80 acts as a signaling scaffold: it recruits Src-family kinases into the complex to enable G-protein-independent, substance-P-driven activation of NALCN [PMID:19092807, PMID:19535918], while the complex also couples extracellular Ca2+ sensing to a Na+-leak current [PMID:21040849]. A missense mutation (p.Pro1700Ser) in UNC80 markedly reduces NALCN currents, linking UNC80 to human disease [PMID:26708751], and UNC80 knockout mice are neonatal lethal [PMID:32620897]. UNC80 transcripts undergo ADAR2-dependent A-to-I editing in the brain that modulates neuronal excitability and glutamate dynamics [PMID:38892173].","teleology":[{"year":2008,"claim":"Established that UNC-80 is a conserved neuronal protein required to localize the NCA/NALCN cation channels and to propagate depolarization within neurons, defining its role as a channel-positioning factor rather than a pore component.","evidence":"Loss-of-function genetics, immunolocalization, calcium imaging and electrophysiology in C. elegans, including suppressor epistasis with synaptojanin","pmids":["17825559","18336069"],"confidence":"Medium","gaps":["Did not define the molecular interaction surface with the channel","Mechanism of localization not resolved at structural level"]},{"year":2008,"claim":"Showed that UNC-80 is part of a NALCN complex and is required for neuropeptide (substance P, neurotensin) activation of NALCN through a G-protein-independent, Src-kinase-dependent pathway, defining a signaling rather than purely structural function.","evidence":"Patch-clamp in mouse hippocampal and VTA neurons, co-immunoprecipitation, neuropeptide stimulation","pmids":["19092807"],"confidence":"High","gaps":["Did not show direct Src binding to UNC80","GPCR coupling to the kinase pathway not fully resolved"]},{"year":2009,"claim":"Resolved how UNC80 enables G-protein-independent activation by showing it physically binds and recruits Src kinases into the channel complex, framing UNC80 as a kinase scaffold.","evidence":"Co-immunoprecipitation and pulldown assays","pmids":["19535918"],"confidence":"Medium","gaps":["Single method for the Src-binding claim","Binding interface on UNC80 not mapped"]},{"year":2010,"claim":"Demonstrated that UNC80 bridges NALCN to UNC79 and that this tripartite complex couples extracellular Ca2+ sensing to a Na+-leak current, defining the architecture and a second activation input.","evidence":"Patch-clamp in knockout-mouse hippocampal neurons, co-IP, pharmacological dissection of the G-protein pathway","pmids":["21040849"],"confidence":"High","gaps":["Did not localize the UNC79-binding region within UNC80","Reconciliation of G-protein-dependent Ca2+ input with G-protein-independent neuropeptide input unresolved"]},{"year":2013,"claim":"Established interdependent post-transcriptional stabilization among NALCN, UNC79 and UNC80 and a non-redundant requirement for UNC80 in circadian behavior, showing the three subunits function as an obligate module.","evidence":"Co-IP from Drosophila brain, tissue-specific RNAi, rescue experiments, western blot and RT-PCR","pmids":["24223770"],"confidence":"High","gaps":["Mechanism of mutual protein stabilization not defined","Whether stabilization is direct or via complex assembly unknown"]},{"year":2015,"claim":"Provided direct evidence that UNC80 is required for human NALCN channel function by showing a disease-associated missense mutation reduces channel currents.","evidence":"Patch-clamp in transfected HEK293T cells expressing mutant UNC80","pmids":["26708751"],"confidence":"Medium","gaps":["Single mutation tested","Mechanism by which p.Pro1700Ser impairs the complex not defined"]},{"year":2020,"claim":"Localized a UNC80 C-terminal domain that mediates UNC79 binding and overcomes a soma-retention signal to drive dendritic targeting, separating UNC80's localization function from its support of whole-cell currents.","evidence":"Co-IP, domain deletion, live dendritic imaging, patch-clamp, and UNC80 knockout mice","pmids":["32620897"],"confidence":"High","gaps":["Identity of the soma-retention signal and its readers unknown","Structural basis of UNC79 binding not resolved at this stage"]},{"year":2022,"claim":"Resolved the structural mechanism: UNC79-UNC80 form a pillar-shaped heterodimer making tripartite contacts with NALCN, with two contacts governing surface localization and a third relieving auto-inhibition by displacing the CIH.","evidence":"Cryo-EM of the NALCN-FAM155A-UNC79-UNC80 complex with mutagenesis-based functional validation","pmids":["35550517"],"confidence":"High","gaps":["Does not capture the Src-kinase-bound or neuropeptide-activated state","Dynamics of CIH displacement during gating not resolved"]},{"year":2024,"claim":"Showed that UNC80 transcripts are subject to ADAR2-dependent recoding A-to-I editing that tunes neuronal excitability and glutamate dynamics, adding a layer of regulation over the complex.","evidence":"CRISPR knock-in mouse models, in vivo neuronal activity and glutamate measurements, olfactory behavior, transcriptomics","pmids":["38892173"],"confidence":"Medium","gaps":["Effect of the edited residue on UNC80-NALCN biochemistry not defined","Single lab, not yet independently replicated"]},{"year":null,"claim":"How UNC80's distinct activation inputs (Src/neuropeptide vs. G-protein/Ca2+) and its RNA-editing state map onto the structurally defined contacts to dynamically gate NALCN remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of an activated or Src-bound state","Editing site not placed onto the structural model","Causal chain from neuropeptide receptors to UNC80-scaffolded Src not fully reconstituted"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,4,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,6,8]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,8]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,2,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,4]}],"complexes":["NALCN channel complex (NALCN-FAM155A-UNC79-UNC80)"],"partners":["NALCN","UNC79","FAM155A","SRC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N2C7","full_name":"Protein unc-80 homolog","aliases":[],"length_aa":3258,"mass_kda":363.4,"function":"Auxiliary subunit of the NALCN sodium channel complex, a voltage-gated ion channel responsible for the resting Na(+) permeability that controls neuronal excitability (By similarity). Activated by neuropeptides substance P, neurotensin, and extracellular Ca(2+) that regulates neuronal excitability by controlling the sizes of NALCN-dependent sodium-leak current. UNC80 is essential for NALCN sensitivity to extracellular Ca(2+) (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8N2C7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UNC80","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/UNC80","total_profiled":1310},"omim":[{"mim_id":"616884","title":"UNC79 HOMOLOG, NALCN CHANNEL COMPLEX SUBUNIT; UNC79","url":"https://www.omim.org/entry/616884"},{"mim_id":"616801","title":"HYPOTONIA, INFANTILE, WITH PSYCHOMOTOR RETARDATION AND CHARACTERISTIC FACIES 2; IHPRF2","url":"https://www.omim.org/entry/616801"},{"mim_id":"615419","title":"HYPOTONIA, INFANTILE, WITH PSYCHOMOTOR RETARDATION AND CHARACTERISTIC FACIES 1; IHPRF1","url":"https://www.omim.org/entry/615419"},{"mim_id":"612636","title":"UNC80 HOMOLOG, NALCN CHANNEL COMPLEX SUBUNIT; UNC80","url":"https://www.omim.org/entry/612636"},{"mim_id":"611549","title":"SODIUM LEAK CHANNEL, NONSELECTIVE; NALCN","url":"https://www.omim.org/entry/611549"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear bodies","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":29.7},{"tissue":"pituitary gland","ntpm":12.8},{"tissue":"retina","ntpm":17.6}],"url":"https://www.proteinatlas.org/search/UNC80"},"hgnc":{"alias_symbol":["FLJ33496","KIAA1843","UNC-80"],"prev_symbol":["C2orf21"]},"alphafold":{"accession":"Q8N2C7","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N2C7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N2C7-6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N2C7-6-F1-predicted_aligned_error_v6.png","plddt_mean":73.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UNC80","jax_strain_url":"https://www.jax.org/strain/search?query=UNC80"},"sequence":{"accession":"Q8N2C7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N2C7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N2C7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N2C7"}},"corpus_meta":[{"pmid":"21040849","id":"PMC_21040849","title":"Extracellular calcium controls background current and neuronal excitability via an UNC79-UNC80-NALCN cation channel complex.","date":"2010","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/21040849","citation_count":163,"is_preprint":false},{"pmid":"19092807","id":"PMC_19092807","title":"Peptide neurotransmitters activate a cation channel complex of NALCN and UNC-80.","date":"2008","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/19092807","citation_count":130,"is_preprint":false},{"pmid":"18336069","id":"PMC_18336069","title":"A putative cation channel, NCA-1, and a novel protein, UNC-80, transmit neuronal activity in C. elegans.","date":"2008","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/18336069","citation_count":99,"is_preprint":false},{"pmid":"17825559","id":"PMC_17825559","title":"UNC-80 and the NCA ion channels contribute to endocytosis defects in synaptojanin mutants.","date":"2007","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/17825559","citation_count":74,"is_preprint":false},{"pmid":"26545877","id":"PMC_26545877","title":"UNC80 mutation causes a syndrome of hypotonia, severe intellectual disability, dyskinesia and dysmorphism, similar to that caused by mutations in its interacting cation channel NALCN.","date":"2015","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26545877","citation_count":42,"is_preprint":false},{"pmid":"26708751","id":"PMC_26708751","title":"Biallelic Mutations in UNC80 Cause Persistent Hypotonia, Encephalopathy, Growth Retardation, and Severe Intellectual Disability.","date":"2015","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26708751","citation_count":42,"is_preprint":false},{"pmid":"30167850","id":"PMC_30167850","title":"Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies).","date":"2018","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30167850","citation_count":41,"is_preprint":false},{"pmid":"24223770","id":"PMC_24223770","title":"UNC79 and UNC80, putative auxiliary subunits of the NARROW ABDOMEN ion channel, are indispensable for robust circadian locomotor rhythms in Drosophila.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24223770","citation_count":38,"is_preprint":false},{"pmid":"26708753","id":"PMC_26708753","title":"Mutations in UNC80, Encoding Part of the UNC79-UNC80-NALCN Channel Complex, Cause Autosomal-Recessive Severe Infantile Encephalopathy.","date":"2015","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26708753","citation_count":38,"is_preprint":false},{"pmid":"35550517","id":"PMC_35550517","title":"Structure and mechanism of NALCN-FAM155A-UNC79-UNC80 channel complex.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35550517","citation_count":26,"is_preprint":false},{"pmid":"19535918","id":"PMC_19535918","title":"UNC80 functions as a scaffold for Src kinases in NALCN channel function.","date":"2009","source":"Channels (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/19535918","citation_count":24,"is_preprint":false},{"pmid":"32620897","id":"PMC_32620897","title":"Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32620897","citation_count":22,"is_preprint":false},{"pmid":"29430593","id":"PMC_29430593","title":"Identification of a novel homozygous UNC80 variant in a child with infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2).","date":"2018","source":"Metabolic brain disease","url":"https://pubmed.ncbi.nlm.nih.gov/29430593","citation_count":14,"is_preprint":false},{"pmid":"30771478","id":"PMC_30771478","title":"Whole exome sequencing revealed mutations in FBXL4, UNC80, and ADK in Thai patients with severe intellectual disabilities.","date":"2019","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/30771478","citation_count":14,"is_preprint":false},{"pmid":"34594366","id":"PMC_34594366","title":"Case Report: Complete Maternal Uniparental Disomy of Chromosome 2 With a Novel UNC80 Splicing Variant c.5609-4G> A in a Chinese Patient With Infantile Hypotonia With Psychomotor Retardation and Characteristic Facies 2.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34594366","citation_count":7,"is_preprint":false},{"pmid":"37067163","id":"PMC_37067163","title":"Novel nonsense mutation in UNC80 in a Turkish patient further validates the sociable skill and severe gastrointestinal problems as part of disease spectrum.","date":"2023","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/37067163","citation_count":4,"is_preprint":false},{"pmid":"31223553","id":"PMC_31223553","title":"Atypical Presentation of Viral Gastroenteritis in a Three-year-old Child Due to a UNC80 Mutation.","date":"2019","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/31223553","citation_count":4,"is_preprint":false},{"pmid":"30092901","id":"PMC_30092901","title":"Case Report of Pediatric Channelopathies With UNC80 and KCNJ11 Mutations Having Abnormal Respiratory Control Treated With Positive Airway Pressure Therapy.","date":"2018","source":"Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30092901","citation_count":4,"is_preprint":false},{"pmid":"38892173","id":"PMC_38892173","title":"Imbalance in Unc80 RNA Editing Disrupts Dynamic Neuronal Activity and Olfactory Perception.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38892173","citation_count":1,"is_preprint":false},{"pmid":"41458659","id":"PMC_41458659","title":"Clinical Utility of Whole-Exome Sequencing in a Consanguineous Family with UNC80-related Neurodevelopmental Disorder: A Case Series and Review of the Literature.","date":"2025","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/41458659","citation_count":0,"is_preprint":false},{"pmid":"40801661","id":"PMC_40801661","title":"Integrated Genomic Approach: A Five Exon Intragenic Deletion in UNC80 Combines With a Novel Splice Variant to Cause IHPRF2 Syndrome in an Italian Family.","date":"2025","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/40801661","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.04.647097","title":"NALCN/Cch1 channelosome subunits originated in early eukaryotes and are fully conserved in animals, fungi, and apusomonads","date":"2025-04-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.04.647097","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11479,"output_tokens":2570,"usd":0.036493,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9712,"output_tokens":3205,"usd":0.064342,"stage2_stop_reason":"end_turn"},"total_usd":0.100835,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"UNC-80 is required for proper localization of NCA-1 and NCA-2 ion channel subunits in C. elegans neurons; loss of unc-80 mislocalizes these channels, and unc-80 mutants suppress locomotory, vesicle depletion, and electrophysiological defects of synaptojanin mutants, placing UNC-80 downstream of PIP2 accumulation in synaptic vesicle recycling.\",\n      \"method\": \"Genetic suppressor screen in C. elegans; immunolocalization of NCA-1/NCA-2; electrophysiology\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with clean loss-of-function, localization experiments, and electrophysiology in single lab\",\n      \"pmids\": [\"17825559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In C. elegans, UNC-80 is a novel conserved neuronal protein enriched at nonsynaptic regions that is required for NCA-1 localization along axons and for the propagation of depolarization signals from cell bodies to synapses; UNC-80 function and localization depend on UNC-79.\",\n      \"method\": \"Loss-of-function genetics in C. elegans; in vivo calcium imaging; immunolocalization\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (genetics, calcium imaging, localization) in single lab\",\n      \"pmids\": [\"18336069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"UNC-80 forms a complex with the NALCN cation channel and is required for activation of NALCN by substance P and neurotensin in mouse hippocampal and VTA neurons; this activation occurs through a G-protein-independent mechanism dependent on Src family kinases.\",\n      \"method\": \"Whole-cell patch-clamp electrophysiology in mouse neurons; co-immunoprecipitation; neuropeptide stimulation assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, electrophysiology with defined pharmacology, replicated across two neuron types, published in high-impact journal\",\n      \"pmids\": [\"19092807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"UNC80 physically binds Src kinases and recruits Src into the NALCN channel complex, functioning as a scaffold for Src kinases to enable G-protein-independent activation of NALCN by substance P.\",\n      \"method\": \"Co-immunoprecipitation; pulldown assays\",\n      \"journal\": \"Channels (Austin, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP evidence from single lab, consistent with prior electrophysiology data, but single method for the specific Src binding claim\",\n      \"pmids\": [\"19535918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"UNC80 bridges NALCN to UNC79 within the same channel complex, and this UNC79-UNC80-NALCN complex is required for coupling extracellular Ca2+ sensing (via a Ca2+-sensing GPCR and G-protein activation) to activation of a Na+-leak current in hippocampal neurons; loss of unc79 or nalcn abolishes the [Ca2+]e-dependent I(L-Na).\",\n      \"method\": \"Whole-cell patch-clamp in cultured hippocampal neurons from knockout mice; co-immunoprecipitation; pharmacological dissection of G-protein pathway\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse electrophysiology, Co-IP, pharmacological rescue, multiple orthogonal methods in single well-controlled study\",\n      \"pmids\": [\"21040849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In Drosophila, UNC80 (CG18437) forms a complex with NA (NALCN ortholog) and UNC79 in brain neurons; loss of unc80 phenocopies na mutant circadian locomotor rhythm defects; UNC79, UNC80, and NA show interdependent post-transcriptional regulation such that loss of any one reduces protein (but not transcript) levels of all three; UNC80 requirement for rhythmicity cannot be bypassed by increased NA expression nor substituted by UNC79.\",\n      \"method\": \"Immunoprecipitation from Drosophila brain; tissue-specific RNAi; genetic rescue experiments; western blotting and RT-PCR\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, genetic epistasis, RNAi rescue, protein/transcript analysis with multiple orthogonal methods in single study\",\n      \"pmids\": [\"24223770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A missense mutation (p.Pro1700Ser) in UNC80 markedly decreases NALCN channel currents in HEK293T cells, demonstrating that UNC80 is required for NALCN channel function.\",\n      \"method\": \"Patch-clamp electrophysiology in transfected HEK293T cells expressing mutant UNC80\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional electrophysiology with disease-associated mutant, single lab, single mutation tested\",\n      \"pmids\": [\"26708751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UNC80 and UNC79 are bona fide subunits of the NALCN complex; the C-terminus of UNC80 contains a domain that interacts with UNC79 and is required to overcome a soma-retention signal to achieve dendritic localization of the complex; UNC80 lacking this C-terminal domain still supports whole-cell NALCN currents but loses dendritic localization, implicating the UNC79-UNC80 interaction in regulation of dendritic membrane potential; UNC80 knockout mice are neonatal lethal.\",\n      \"method\": \"Co-immunoprecipitation; domain deletion analysis; live imaging of dendritic localization; whole-cell patch-clamp electrophysiology; UNC80 knockout mice\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mutagenesis, localization imaging with functional electrophysiology, knockout lethality, multiple orthogonal methods in single study\",\n      \"pmids\": [\"32620897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structure of the mammalian NALCN-FAM155A-UNC79-UNC80 quaternary complex reveals that UNC79 and UNC80 form a large pillar-shaped heterodimer tethered to the intracellular side of NALCN through tripartite interactions with cytoplasmic loops of NALCN; two of these interactions are essential for proper cell surface localization of NALCN; the third interaction relieves NALCN self-inhibition by pulling the auto-inhibitory CTD Interacting Helix (CIH) out of its binding site.\",\n      \"method\": \"Cryo-EM structure determination; functional validation of localization and channel activity by mutagenesis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with mutagenesis-based functional validation of multiple interaction sites and mechanism\",\n      \"pmids\": [\"35550517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UNC80 undergoes A-to-I RNA editing at a codon-altering site in the brain in an ADAR2-dependent manner; gain-of-editing knock-in mice (Unc80G/G) show heightened basal neuronal activity in olfactory regions and increased glutamate levels in the olfactory bulb compared to loss-of-editing mice (Unc80S/S), indicating the editing event modulates neuronal excitability and neurotransmitter dynamics.\",\n      \"method\": \"CRISPR/Cas9 knock-in mouse models; in vivo neuronal activity measurements; glutamate level quantification; behavioral olfaction assays; transcriptomic analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR knock-in models with multiple physiological readouts, single lab, novel finding not yet replicated\",\n      \"pmids\": [\"38892173\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UNC80 is a large cytoplasmic auxiliary subunit of the NALCN sodium-leak channel complex that physically bridges NALCN to UNC79 via its C-terminal domain; the cryo-EM structure shows UNC79-UNC80 form a pillar-shaped heterodimer docked to NALCN's intracellular loops through tripartite contacts that promote NALCN cell-surface localization and relieve NALCN auto-inhibition, while UNC80 also scaffolds Src kinases into the complex to enable G-protein-independent, substance-P-receptor-driven channel activation, and its C-terminus is required for dendritic (rather than somatic) localization of the complex to regulate dendritic membrane potential.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UNC80 is a large cytoplasmic auxiliary subunit of the NALCN sodium-leak channel complex that scaffolds the channel and controls its localization and gating in neurons [#2, #7]. It bridges NALCN to UNC79, forming a pillar-shaped UNC79-UNC80 heterodimer that docks onto the intracellular loops of NALCN through tripartite contacts; two of these contacts drive NALCN cell-surface localization while the third relieves NALCN auto-inhibition by extracting the channel's auto-inhibitory CTD-interacting helix from its binding site [#8]. UNC80, UNC79, and NALCN are mutually interdependent for stability, with loss of any one reducing protein levels of all three [#5], and in C. elegans UNC-80 is required for axonal localization of the channel and for propagation of depolarization from cell body to synapse [#0, #1]. A C-terminal domain of UNC80 mediates the UNC79 interaction and overcomes a soma-retention signal to achieve dendritic localization of the complex, thereby regulating dendritic membrane potential [#7]. Beyond its structural role, UNC80 acts as a signaling scaffold: it recruits Src-family kinases into the complex to enable G-protein-independent, substance-P-driven activation of NALCN [#2, #3], while the complex also couples extracellular Ca2+ sensing to a Na+-leak current [#4]. A missense mutation (p.Pro1700Ser) in UNC80 markedly reduces NALCN currents, linking UNC80 to human disease [#6], and UNC80 knockout mice are neonatal lethal [#7]. UNC80 transcripts undergo ADAR2-dependent A-to-I editing in the brain that modulates neuronal excitability and glutamate dynamics [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that UNC-80 is a conserved neuronal protein required to localize the NCA/NALCN cation channels and to propagate depolarization within neurons, defining its role as a channel-positioning factor rather than a pore component.\",\n      \"evidence\": \"Loss-of-function genetics, immunolocalization, calcium imaging and electrophysiology in C. elegans, including suppressor epistasis with synaptojanin\",\n      \"pmids\": [\"17825559\", \"18336069\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the molecular interaction surface with the channel\", \"Mechanism of localization not resolved at structural level\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed that UNC-80 is part of a NALCN complex and is required for neuropeptide (substance P, neurotensin) activation of NALCN through a G-protein-independent, Src-kinase-dependent pathway, defining a signaling rather than purely structural function.\",\n      \"evidence\": \"Patch-clamp in mouse hippocampal and VTA neurons, co-immunoprecipitation, neuropeptide stimulation\",\n      \"pmids\": [\"19092807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not show direct Src binding to UNC80\", \"GPCR coupling to the kinase pathway not fully resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved how UNC80 enables G-protein-independent activation by showing it physically binds and recruits Src kinases into the channel complex, framing UNC80 as a kinase scaffold.\",\n      \"evidence\": \"Co-immunoprecipitation and pulldown assays\",\n      \"pmids\": [\"19535918\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method for the Src-binding claim\", \"Binding interface on UNC80 not mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated that UNC80 bridges NALCN to UNC79 and that this tripartite complex couples extracellular Ca2+ sensing to a Na+-leak current, defining the architecture and a second activation input.\",\n      \"evidence\": \"Patch-clamp in knockout-mouse hippocampal neurons, co-IP, pharmacological dissection of the G-protein pathway\",\n      \"pmids\": [\"21040849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not localize the UNC79-binding region within UNC80\", \"Reconciliation of G-protein-dependent Ca2+ input with G-protein-independent neuropeptide input unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established interdependent post-transcriptional stabilization among NALCN, UNC79 and UNC80 and a non-redundant requirement for UNC80 in circadian behavior, showing the three subunits function as an obligate module.\",\n      \"evidence\": \"Co-IP from Drosophila brain, tissue-specific RNAi, rescue experiments, western blot and RT-PCR\",\n      \"pmids\": [\"24223770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of mutual protein stabilization not defined\", \"Whether stabilization is direct or via complex assembly unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided direct evidence that UNC80 is required for human NALCN channel function by showing a disease-associated missense mutation reduces channel currents.\",\n      \"evidence\": \"Patch-clamp in transfected HEK293T cells expressing mutant UNC80\",\n      \"pmids\": [\"26708751\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single mutation tested\", \"Mechanism by which p.Pro1700Ser impairs the complex not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Localized a UNC80 C-terminal domain that mediates UNC79 binding and overcomes a soma-retention signal to drive dendritic targeting, separating UNC80's localization function from its support of whole-cell currents.\",\n      \"evidence\": \"Co-IP, domain deletion, live dendritic imaging, patch-clamp, and UNC80 knockout mice\",\n      \"pmids\": [\"32620897\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the soma-retention signal and its readers unknown\", \"Structural basis of UNC79 binding not resolved at this stage\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved the structural mechanism: UNC79-UNC80 form a pillar-shaped heterodimer making tripartite contacts with NALCN, with two contacts governing surface localization and a third relieving auto-inhibition by displacing the CIH.\",\n      \"evidence\": \"Cryo-EM of the NALCN-FAM155A-UNC79-UNC80 complex with mutagenesis-based functional validation\",\n      \"pmids\": [\"35550517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not capture the Src-kinase-bound or neuropeptide-activated state\", \"Dynamics of CIH displacement during gating not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed that UNC80 transcripts are subject to ADAR2-dependent recoding A-to-I editing that tunes neuronal excitability and glutamate dynamics, adding a layer of regulation over the complex.\",\n      \"evidence\": \"CRISPR knock-in mouse models, in vivo neuronal activity and glutamate measurements, olfactory behavior, transcriptomics\",\n      \"pmids\": [\"38892173\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect of the edited residue on UNC80-NALCN biochemistry not defined\", \"Single lab, not yet independently replicated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How UNC80's distinct activation inputs (Src/neuropeptide vs. G-protein/Ca2+) and its RNA-editing state map onto the structurally defined contacts to dynamically gate NALCN remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of an activated or Src-bound state\", \"Editing site not placed onto the structural model\", \"Causal chain from neuropeptide receptors to UNC80-scaffolded Src not fully reconstituted\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 6, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 4]}\n    ],\n    \"complexes\": [\"NALCN channel complex (NALCN-FAM155A-UNC79-UNC80)\"],\n    \"partners\": [\"NALCN\", \"UNC79\", \"FAM155A\", \"SRC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}