Affinage

UNC80

Protein unc-80 homolog · UniProt Q8N2C7

Length
3258 aa
Mass
363.4 kDa
Annotated
2026-06-10
21 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2008 Medium

    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

    PMID:17825559 PMID:18336069

    Open questions at the time
    • Did not define the molecular interaction surface with the channel
    • Mechanism of localization not resolved at structural level
  2. 2008 High

    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

    PMID:19092807

    Open questions at the time
    • Did not show direct Src binding to UNC80
    • GPCR coupling to the kinase pathway not fully resolved
  3. 2009 Medium

    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

    PMID:19535918

    Open questions at the time
    • Single method for the Src-binding claim
    • Binding interface on UNC80 not mapped
  4. 2010 High

    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

    PMID:21040849

    Open questions at the time
    • Did not localize the UNC79-binding region within UNC80
    • Reconciliation of G-protein-dependent Ca2+ input with G-protein-independent neuropeptide input unresolved
  5. 2013 High

    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

    PMID:24223770

    Open questions at the time
    • Mechanism of mutual protein stabilization not defined
    • Whether stabilization is direct or via complex assembly unknown
  6. 2015 Medium

    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

    PMID:26708751

    Open questions at the time
    • Single mutation tested
    • Mechanism by which p.Pro1700Ser impairs the complex not defined
  7. 2020 High

    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

    PMID:32620897

    Open questions at the time
    • Identity of the soma-retention signal and its readers unknown
    • Structural basis of UNC79 binding not resolved at this stage
  8. 2022 High

    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

    PMID:35550517

    Open questions at the time
    • Does not capture the Src-kinase-bound or neuropeptide-activated state
    • Dynamics of CIH displacement during gating not resolved
  9. 2024 Medium

    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

    PMID:38892173

    Open questions at the time
    • Effect of the edited residue on UNC80-NALCN biochemistry not defined
    • Single lab, not yet independently replicated

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3
Partners
FAM155ANALCNSRCUNC79
Complex memberships
NALCN channel complex (NALCN-FAM155A-UNC79-UNC80)

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 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. Genetic suppressor screen in C. elegans; immunolocalization of NCA-1/NCA-2; electrophysiology Current biology : CB Medium 17825559
2008 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. Loss-of-function genetics in C. elegans; in vivo calcium imaging; immunolocalization PLoS biology Medium 18336069
2008 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. Whole-cell patch-clamp electrophysiology in mouse neurons; co-immunoprecipitation; neuropeptide stimulation assays Nature High 19092807
2009 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. Co-immunoprecipitation; pulldown assays Channels (Austin, Tex.) Medium 19535918
2010 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). Whole-cell patch-clamp in cultured hippocampal neurons from knockout mice; co-immunoprecipitation; pharmacological dissection of G-protein pathway Neuron High 21040849
2013 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. Immunoprecipitation from Drosophila brain; tissue-specific RNAi; genetic rescue experiments; western blotting and RT-PCR PloS one High 24223770
2015 A missense mutation (p.Pro1700Ser) in UNC80 markedly decreases NALCN channel currents in HEK293T cells, demonstrating that UNC80 is required for NALCN channel function. Patch-clamp electrophysiology in transfected HEK293T cells expressing mutant UNC80 American journal of human genetics Medium 26708751
2020 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. Co-immunoprecipitation; domain deletion analysis; live imaging of dendritic localization; whole-cell patch-clamp electrophysiology; UNC80 knockout mice Nature communications High 32620897
2022 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. Cryo-EM structure determination; functional validation of localization and channel activity by mutagenesis Nature communications High 35550517
2024 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. CRISPR/Cas9 knock-in mouse models; in vivo neuronal activity measurements; glutamate level quantification; behavioral olfaction assays; transcriptomic analysis International journal of molecular sciences Medium 38892173

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Extracellular calcium controls background current and neuronal excitability via an UNC79-UNC80-NALCN cation channel complex. Neuron 163 21040849
2008 Peptide neurotransmitters activate a cation channel complex of NALCN and UNC-80. Nature 130 19092807
2008 A putative cation channel, NCA-1, and a novel protein, UNC-80, transmit neuronal activity in C. elegans. PLoS biology 99 18336069
2007 UNC-80 and the NCA ion channels contribute to endocytosis defects in synaptojanin mutants. Current biology : CB 74 17825559
2015 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. Journal of medical genetics 42 26545877
2015 Biallelic Mutations in UNC80 Cause Persistent Hypotonia, Encephalopathy, Growth Retardation, and Severe Intellectual Disability. American journal of human genetics 42 26708751
2018 Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies). Human genetics 41 30167850
2015 Mutations in UNC80, Encoding Part of the UNC79-UNC80-NALCN Channel Complex, Cause Autosomal-Recessive Severe Infantile Encephalopathy. American journal of human genetics 38 26708753
2013 UNC79 and UNC80, putative auxiliary subunits of the NARROW ABDOMEN ion channel, are indispensable for robust circadian locomotor rhythms in Drosophila. PloS one 38 24223770
2022 Structure and mechanism of NALCN-FAM155A-UNC79-UNC80 channel complex. Nature communications 26 35550517
2009 UNC80 functions as a scaffold for Src kinases in NALCN channel function. Channels (Austin, Tex.) 24 19535918
2020 Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex. Nature communications 22 32620897
2019 Whole exome sequencing revealed mutations in FBXL4, UNC80, and ADK in Thai patients with severe intellectual disabilities. Gene 14 30771478
2018 Identification of a novel homozygous UNC80 variant in a child with infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2). Metabolic brain disease 14 29430593
2021 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. Frontiers in genetics 7 34594366
2023 Novel nonsense mutation in UNC80 in a Turkish patient further validates the sociable skill and severe gastrointestinal problems as part of disease spectrum. American journal of medical genetics. Part A 4 37067163
2019 Atypical Presentation of Viral Gastroenteritis in a Three-year-old Child Due to a UNC80 Mutation. Cureus 4 31223553
2018 Case Report of Pediatric Channelopathies With UNC80 and KCNJ11 Mutations Having Abnormal Respiratory Control Treated With Positive Airway Pressure Therapy. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine 4 30092901
2024 Imbalance in Unc80 RNA Editing Disrupts Dynamic Neuronal Activity and Olfactory Perception. International journal of molecular sciences 1 38892173
2025 Integrated Genomic Approach: A Five Exon Intragenic Deletion in UNC80 Combines With a Novel Splice Variant to Cause IHPRF2 Syndrome in an Italian Family. American journal of medical genetics. Part A 0 40801661
2025 Clinical Utility of Whole-Exome Sequencing in a Consanguineous Family with UNC80-related Neurodevelopmental Disorder: A Case Series and Review of the Literature. Cureus 0 41458659

Missed literature

Know a paper Affinage missed for UNC80? Flag it for the maintainers and the community.

No submissions yet.