| 2022 |
Cryo-EM structure of the mammalian NALCN-FAM155A-UNC79-UNC80 quaternary complex shows 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, while a third relieves NALCN self-inhibition by pulling an auto-inhibitory CTD Interacting Helix (CIH) out of its binding site. |
Cryo-EM structure determination with functional validation |
Nature communications |
High |
35550517
|
| 2010 |
UNC79 is a component of a NALCN channel complex in which UNC80 bridges NALCN to UNC79. This complex is required for a G protein-dependent Na+-leak current (I_L-Na) that is activated by lowering extracellular Ca2+. Neurons from unc79 knockout mice lack sensitivity of I_L-Na to changes in extracellular Ca2+, and the excitatory effect of reduced extracellular Ca2+ is absent. |
Knockout mouse electrophysiology (cultured hippocampal neurons), genetic analysis, Ca2+ sensitivity assay |
Neuron |
High |
21040849
|
| 2020 |
UNC79 and UNC80 are bona fide subunits of the NALCN channel complex in mammals. The C-terminus of UNC80 contains a domain that interacts with UNC79 and is required for dendritic localization of the complex; UNC80 lacking this domain (as found in intellectual disability patients) still supports whole-cell NALCN currents but fails to localize to dendrites, implicating UNC79 interaction in dendritic membrane potential regulation. |
UNC80 knockout mice (neonatal lethal phenotype confirmed), domain-deletion constructs, Co-immunoprecipitation, subcellular localization imaging, whole-cell patch-clamp |
Nature communications |
High |
32620897
|
| 2007 |
UNC-79 encodes a large cytosolic protein that controls NA (NALCN ortholog) protein levels by a post-transcriptional mechanism in both Drosophila and C. elegans. Biochemical studies show that loss of UNC-79 reduces NA protein without affecting transcript levels, placing UNC-79 upstream of the channel in a conserved pathway also involving the na/NALCN gene. |
Genetic epistasis (double mutants), biochemical assay of protein vs. mRNA levels, cross-species ortholog analysis |
Current biology : CB |
High |
17350263
|
| 2013 |
In Drosophila, UNC79 and UNC80 are required for robust circadian locomotor rhythmicity in pacemaker neurons. Loss of unc79, unc80, or na leads to decreased expression of all three proteins with minimal effect on transcript levels, demonstrating an interdependent post-transcriptional regulatory relationship. Immunoprecipitation confirms that UNC79 and UNC80 form a complex with NA (NALCN ortholog) in the Drosophila brain. Functional requirements for UNC79 and UNC80 extend beyond merely promoting channel subunit expression, as increased NA protein cannot bypass the need for these subunits. |
Genetic loss-of-function alleles, tissue-specific RNAi and rescue, immunoprecipitation, protein and transcript quantification |
PloS one |
High |
24223770
|
| 2008 |
In C. elegans, NCA-1 localization along axons and its function in propagating neuronal activity from cell bodies to synapses depend on UNC-79 and UNC-80. Loss of UNC-79 disrupts NCA-1 localization (enriched at nonsynaptic regions) and reduces synaptic calcium transients at neuromuscular junctions. |
In vivo calcium imaging, fluorescent protein localization, genetic loss-of-function analysis |
PLoS biology |
High |
18336069
|
| 2010 |
Positional cloning of the mouse Lightweight (Lwt) mutation identifies it as a loss-of-function allele in the mouse UNC79 homolog. Lwt/Lwt homozygotes are perinatal lethal; heterozygotes are hypersensitive to acute ethanol and to the anesthetic isoflurane. Parallel C. elegans experiments confirm conserved hypersensitivity to ethanol in unc-79 mutants and in nca-1;nca-2 double mutants, placing UNC79 in the same pathway as NCA/NALCN channels. |
ENU forward mutagenesis, positional cloning, behavioral pharmacology (ethanol/isoflurane), genetic epistasis in C. elegans |
PLoS genetics |
High |
20714347
|
| 2020 |
Robust functional expression of the NALCN channel complex in heterologous systems requires co-expression of UNC79, UNC80, and FAM155A. The resulting complex is constitutively active, conducts monovalent cations, and is blocked by physiological concentrations of extracellular divalent cations; it also shows voltage-dependent modulation. |
Heterologous expression (co-transfection), electrophysiology (whole-cell and single-channel recordings), pharmacological profiling |
Science advances |
High |
32494638
|
| 2006 |
Targeted disruption of mouse KIAA1409 (UNC79 homolog) results in mice that lack the ability to drink (adipsia phenotype), establishing that UNC79 is essential for a specific neural behavior in mammals. Homozygous knockouts display this overt phenotypic defect. |
Gene-targeted knockout mice, behavioral phenotyping |
FASEB journal |
Medium |
16807365
|
| 2008 |
In C. elegans, unc-79 and unc-80 mutants are defective in NCA ion channel stabilization and in transitioning between crawling and swimming locomotor rhythms, placing UNC-79 genetically upstream or in the same pathway as NCA channels for behavioral pattern generation. |
Genetic mutant analysis, in vivo calcium imaging, behavioral assays |
Proceedings of the National Academy of Sciences |
Medium |
19074276
|
| 1987 |
Mutations in unc-79 confer hypersensitivity to halothane in C. elegans. The double mutant unc-79; unc-80 is slightly more sensitive than either single mutant, suggesting additive or partially redundant functions, and mutations in unc-9 suppress both unc-79 and unc-80 halothane hypersensitivity, placing these genes in a genetic pathway. |
Genetic mutant analysis, anesthetic dose-response (ED50 determination), epistasis with suppressor mutations |
Science |
Medium |
3576211
|
| 2021 |
In Drosophila, UNC79 functions within mushroom body neurons (distinct from pacemaker neurons) to regulate sleep duration and starvation resistance, revealing a spatially separable role from its function in circadian rhythmicity in pacemaker neurons. |
Genetic knockdown (RNAi), tissue-specific rescue, sleep/behavioral assays, starvation resistance assays |
G3 (Bethesda, Md.) |
Medium |
34849820
|
| 2023 |
Heterozygous loss-of-function variants in UNC79 in humans are associated with a neurodevelopmental syndrome. Drosophila with UNC79 knocked down display induced seizure-like phenotypes, and heterozygous loss-of-function mice show developmental delay in body weight and impaired learning and memory, establishing UNC79 haploinsufficiency as causally linked to neurological pathology. |
Human genetics, Drosophila RNAi seizure assay, heterozygous mouse KO behavioral testing (learning/memory, body weight) |
Genetics in medicine |
Medium |
37183800
|
| 2018 |
Loss of UNC-79 in C. elegans robustly increases arousal thresholds during sleep bouts in L4-to-adult developmentally timed sleep, and this effect is suppressed by loss of EGL-4 or innexin proteins (UNC-7, UNC-9), placing UNC-79/NCA channels upstream of gap junctions in a sleep-regulation pathway. |
Genetic epistasis, behavioral sleep assays, arousal threshold measurement |
Genetics |
Medium |
30323068
|