Affinage

GNAO1

Guanine nucleotide-binding protein G(o) subunit alpha · UniProt P09471

Length
354 aa
Mass
40.1 kDa
Annotated
2026-06-10
100 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GNAO1 encodes Gαo, a pertussis toxin-sensitive heterotrimeric G protein α-subunit that serves as the immediate transducer downstream of numerous neuronal GPCRs and couples receptor activation to ion-channel and cytoskeletal control (PMID:7932231, PMID:10693938). As a guanine-nucleotide switch, Gαo cycles between GDP-bound (receptor-associated, inactive heterotrimer) and GTP-bound active states; its nucleotide-binding conformation is governed by the N-terminal region and switch elements, and its C-terminal -3 glycine constrains productive receptor coupling (PMID:7727415, PMID:11562427). In sensory and neuronal circuits Gαo is functionally non-redundant: it is required for the mGluR6-driven light response of retinal ON bipolar cells (PMID:11124982), for V2R-receptor-mediated vomeronasal pheromone detection and associated aggression behaviors (PMID:21768373), and for muscarinic and α-adrenergic inhibition of neuronal and cardiac Ca2+ channels, in part through direct N-terminal binding to the Cav2.1 C-terminus (PMID:9050846, PMID:7932231, PMID:11395521). Beyond channel modulation, Gαo drives morphogenetic signaling—promoting neurite outgrowth by targeting Rap1GAPII for proteasomal degradation to activate a Rap1→Ral→Src→Stat3 cascade and a parallel Rho-GTPase→JNK arm downstream of CB1 and WNT/Frizzled receptors (PMID:15657046, PMID:16046413, PMID:18187455), and acting upstream of Rho-ROCK to control growth-cone formation and neuronal polarity (PMID:39048611). Gαo also negatively regulates Schwann cell myelination by suppressing cAMP and PI3K/AKT (PMID:38331815) and sets cardiac Ca2+ homeostasis as a transcriptional target of NRSF (PMID:34875852). Its GTPase cycle is accelerated by RGS proteins acting as GAPs (PMID:12354761, PMID:24700286), and the protein is a direct oxidative-stress sensor, with H2O2 modifying Gαo to drive subunit dissociation and Gβγ-dependent ERK activation (PMID:11100733). De novo GNAO1 mutations cause a spectrum of pediatric encephalopathies: loss-of-function alleles that impair plasma-membrane localization and receptor-mediated cAMP/Ca2+ signaling associate with epileptic encephalopathy, whereas gain-of-function and conformation-altering alleles—which accelerate GTP uptake, abolish hydrolysis by displacing the catalytic glutamine, and acquire neomorphic interactions with Ric8 chaperones—associate with hyperkinetic movement disorders, with disease severity correlating with the strength of aberrant Gαo-Ric8B binding (PMID:23993195, PMID:28747448, PMID:36206333, PMID:38874642). Distinct N-terminal helix-destabilizing substitutions that block heterotrimer formation produce a parkinsonian phenotype (PMID:38358016).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1989 Medium

    Established that Gαo exists as biochemically distinct purifiable isoforms in brain, providing the protein substrate for all subsequent functional work.

    Evidence Protein purification and peptide mapping of two Gαo isoforms from bovine brain

    PMID:2506013

    Open questions at the time
    • Functional differences between Gαo-I and Gαo-II not resolved
    • Tissue distribution of isoforms incomplete
  2. 1995 Medium

    Defined how the nucleotide-binding conformation of Gαo is structurally encoded, showing the N-terminal region and specific hydrophobic C-terminal contacts govern GDP affinity and the activated state.

    Evidence In vitro chimera and deletion analysis of Gαo/Gαi2 with proteolysis and nucleotide-binding assays

    PMID:7727415

    Open questions at the time
    • No high-resolution structure of the full switch cycle
    • Did not address GPCR coupling determinants
  3. 1997 High

    Demonstrated that Gαo is the non-redundant transducer of receptor-mediated Ca2+ channel inhibition, ruling out substitution by other Gα subunits.

    Evidence Gαo-null mouse with patch-clamp of ventricular myocytes and sympathetic neuron antibody microinjection

    PMID:7932231 PMID:9050846

    Open questions at the time
    • Molecular basis of channel inhibition (direct vs Gβγ) not distinguished here
    • Effector identity downstream of Gαo unresolved
  4. 2000 High

    Resolved Gαo's roles in a sensory circuit and as a direct redox sensor, showing it is required for the ON bipolar light response and is activated by H2O2 to liberate signaling Gβγ.

    Evidence Gαo-null ERG recordings; in vitro GTPγS binding with purified Go plus cardiomyocyte ERK assays

    PMID:11100733 PMID:11124982

    Open questions at the time
    • Site of oxidative modification on Gαo not mapped
    • Link between retinal requirement and downstream effectors incomplete
  5. 2001 High

    Identified a direct physical mechanism for channel modulation and a structural determinant of receptor coupling, mapping Gαo N-terminus to the Cav2.1 C-terminus and the C-terminal -3 glycine to α2A-adrenoceptor activation.

    Evidence In vitro binding, peptide competition, electrophysiology, and C-terminal mutagenesis with GTPγS binding

    PMID:11395521 PMID:11562427

    Open questions at the time
    • Stoichiometry of Gαo-Cav2.1 binding unknown
    • Generality across channel subtypes untested
  6. 2005 High

    Defined a morphogenetic effector pathway, showing Gαo induces neurite outgrowth by degrading Rap1GAPII to activate a Rap1→Ral→Src→Stat3 cascade with a parallel Rac1/JNK arm.

    Evidence Dominant-negative constructs, proteasome and pathway inhibitors, siRNA, pertussis toxin in Neuro-2A cells

    PMID:15657046 PMID:16046413

    Open questions at the time
    • Mechanism by which Gαo directs Rap1GAPII ubiquitination unknown
    • Relevance to in vivo neuronal development not tested here
  7. 2008 High

    Placed Gαo in WNT planar-cell-polarity signaling and cardiac contractile control, defining a Frizzled→Dvl1/3→RhoA/Rac1/Cdc42→MEKK→JNK axis and a constitutively active cardiac phenotype.

    Evidence siRNA epistasis with DN GTPases in F9 cells; cardiac-specific constitutively active Gαo1* transgenic mice

    PMID:18187455 PMID:18192223

    Open questions at the time
    • Direct Gαo-Dishevelled interaction not biochemically demonstrated
    • PP1 versus PKA contributions in heart only partially separated
  8. 2011 High

    Confirmed the inferred sensory role in vivo and provided the first disease-relevant activating mutation, with conditional KO eliminating V2R responses and the R243H oncogenic mutant accelerating nucleotide exchange.

    Evidence Cre-loxP conditional KO with electrophysiology/behavior; limited proteolysis and GTPase assays with structural analysis

    PMID:21317923 PMID:21768373

    Open questions at the time
    • VNO transduction effectors downstream of Gαo unmapped
    • R243H tumor spectrum and physiological relevance limited
  9. 2013 Medium

    Established GNAO1 as a Mendelian encephalopathy gene, linking de novo mutations to impaired membrane localization and reduced receptor-mediated Ca2+ current inhibition.

    Evidence Whole-exome sequencing, 3D modeling, localization and electrophysiology of transfected mutants

    PMID:23993195

    Open questions at the time
    • Structural predictions were computational
    • Genotype-phenotype mapping incomplete at this stage
  10. 2017 Medium

    Provided a functional dichotomy underlying clinical heterogeneity, separating loss-of-function (epilepsy) from gain-of-function (movement disorder) GNAO1 variants by cAMP inhibition phenotype.

    Evidence Systematic site-directed mutagenesis and cAMP inhibition assays across 15 variants in HEK-293T cells

    PMID:28747448

    Open questions at the time
    • Single signaling readout (cAMP) used to classify
    • Mechanism for normally-functioning mutants causing disease unexplained
  11. 2021 Medium

    Extended mechanistic and physiological scope, defining nucleotide-binding defects and mislocalization for Gln52 mutants, an oncogenic R209C PI3K/mTOR feedback loop, and roles in opioid dependence and NRSF-controlled cardiac Ca2+ handling.

    Evidence Biochemical GTP assays and localization; cell transformation and signaling assays; antisense KD with withdrawal behavior; cardiac NRSF-KO and Gnao1 gain/loss mouse models

    PMID:19460419 PMID:32898863 PMID:34685729 PMID:34875852

    Open questions at the time
    • Partner proteins distinguishing GDP- vs GTP-loaded Gαo not all identified
    • Causal chain from cardiac Gαo to CaMKII activation partly correlative
  12. 2022 Medium

    Unified the biochemical and organismal basis of encephalopathy mutations and revealed therapeutic entry points, showing Gln205 displacement causes constitutive GTP binding, dominant-negative behavior in vivo, and rescue by zinc or adenosine-receptor antagonism.

    Evidence GTP uptake/hydrolysis assays, drug screening, Drosophila zinc rescue, C. elegans CRISPR knock-ins, mouse behavior, aldicarb assays

    PMID:34508586 PMID:34622282 PMID:36206333

    Open questions at the time
    • Aberrant partner interactions only partially characterized
    • Mechanism of zinc rescue at atomic resolution unresolved
  13. 2023 Medium

    Defined how a non-coding GNAO1 mutation produces disease, showing an intronic splice variant inserts two residues into switch III to misconfigure the GTPase machinery while sparing Gβγ and GPCR coupling.

    Evidence Patient lymphoblastoid splicing analysis with biochemical GTP and interaction assays

    PMID:37001522

    Open questions at the time
    • Specific effector interactions altered not fully enumerated
    • In vivo consequences not modeled
  14. 2024 High

    Converged on a neomorphic disease mechanism and refined neuronal and movement-disorder pathophysiology, showing mutant Gαo gains aberrant Ric8A/Ric8B chaperone interactions correlating with severity, acts upstream of Rho-ROCK in neuronal morphogenesis, and produces parkinsonism via heterotrimer-disrupting N-helix substitutions.

    Evidence Co-IP of >80 mutants with localization and clinical correlation; iPSC neurons/organoids with Y27632 rescue; biochemical analysis of purified N-helix mutants; Schwann cell conditional KO

    PMID:38331815 PMID:38358016 PMID:38874642 PMID:39048611

    Open questions at the time
    • How neomorphic Ric8 binding translates to specific clinical features unclear
    • Therapeutic targeting of mutant-Ric8 interaction untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the diverse loss-of-function, gain-of-function, dominant-negative, and neomorphic biochemical defects map onto the distinct clinical phenotypes (epilepsy, hyperkinetic movement disorder, parkinsonism) and which downstream effector imbalance is the proximate driver of each.
  • No unifying model linking specific effector dysregulation to each phenotype
  • Cell-type-specific consequences of mutations not systematically mapped
  • No demonstrated mutation-targeted therapy in patients

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 5 GO:0060089 molecular transducer activity 5 GO:0098772 molecular function regulator activity 3 GO:0140299 molecular sensor activity 1
Localization
GO:0005886 plasma membrane 4 GO:0005794 Golgi apparatus 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 5 R-HSA-112316 Neuronal System 4 R-HSA-1266738 Developmental Biology 4
Partners
CAV2.1DVL1DVL3GNB3RGS19RIC8ARIC8BSPTAN1
Complex memberships
heterotrimeric Go (Gαo/Gβ/Gγ)

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Gαo is required for the light response of ON bipolar neurons in the retina. In Gαo-null mice, the b-wave of the electroretinogram (representing massed ON bipolar cell responses) was entirely absent, while rod/cone photocurrents (a-wave) were normal, establishing that mGluR6 cascade signaling in ON bipolar cells requires Gαo. Knockout mouse (Gαo-/-), electroretinogram recording The Journal of neuroscience High 11124982
1997 Gαo is required for muscarinic inhibition of L-type Ca2+ channels in ventricular myocytes. Gαo-null mice lack muscarinic inhibition of L-type calcium channels, while isoproterenol stimulation and muscarinic regulation of atrial K+ channels remain normal. Other Gα subunits cannot substitute. Homologous recombination knockout mouse, patch-clamp electrophysiology of ventricular myocytes Proceedings of the National Academy of Sciences of the United States of America High 9050846
1994 Gαo (but not Gαq/11 or Gαi1-3) transduces α-adrenoceptor inhibition of Ca2+ current in rat sympathetic (superior cervical ganglion) neurons, as established by microinjection of selective anti-Gαo antibodies which reduced noradrenaline-induced calcium current inhibition. Intraneuronal microinjection of subunit-specific antibodies, electrophysiology The Journal of physiology High 7932231
2000 Gαo is a direct target of reactive oxygen species (H2O2): H2O2 directly activates purified heterotrimeric Go (but not Gs) in vitro by modifying Gαo (not Gβγ), causing subunit dissociation and liberating free Gβγ, which then activates ERK via PI3K and Src in cardiomyocytes. In vitro GTPγS binding assay with purified Go, subunit-specific analysis, cardiomyocyte signaling assays, Gβγ inhibition Nature High 11100733
2001 The N-terminus of Gαo binds to the C-terminus of the α1A (P/Q-type, Cav2.1) Ca2+ channel subunit, and this interaction mediates voltage-resistant inhibition of α1A currents. An anti-Gαo N-terminal antiserum, Gαo N-terminal peptide, and α1A C-terminal peptide all attenuated voltage-resistant inhibition, and in vitro binding was demonstrated. In vitro binding assay, peptide competition, antibody inhibition, electrophysiology The Journal of biological chemistry High 11395521
2011 Gαo is required for vomeronasal sensory neuron function in V2R receptor-expressing (basal layer) neurons. Conditional Gαo deletion from olfactory marker protein-expressing cells eliminated responses to MHC class I antigens, major urinary proteins, exocrine gland-secreting peptide, and N-formylated mitochondrial peptides. Loss of Gαo also abolished male-male territorial aggression and maternal aggression. Cre-loxP conditional knockout, electrophysiology, calcium imaging, behavioral assays Proceedings of the National Academy of Sciences of the United States of America High 21768373
2005 Gαo/i reduces the stability of Rap1GAPII by targeting it for ubiquitination and proteasomal degradation, thereby activating Rap1 and inducing neurite outgrowth downstream of CB1 cannabinoid receptor activation. Proteasomal inhibitor lactacystin blocked Gαo/i-induced Rap1 activation and neurite outgrowth. Dominant-negative Rap1 expression, proteasomal inhibition, siRNA, pertussis toxin treatment, overexpression in Neuro-2A cells The Journal of biological chemistry High 15657046
2005 CB1 receptor signaling through Gαo/i sequentially activates Rap1 → Ral → Src → Stat3, and also Rac1 → JNK → Stat3, to induce neurite outgrowth in Neuro-2A cells. Dominant-negative constructs of Rap1, Ral, Src, and Stat3 each blocked CB1R-induced neurite outgrowth; Ral-DN blocked Gαo-induced Stat3 activation but not v-Src-induced Stat3 activation. Dominant-negative mutant overexpression, pharmacological inhibitors (SP600125), kinase phosphorylation assays, pertussis toxin The Journal of biological chemistry High 16046413
2008 Gαo is required for WNT3a-induced JNK activation in mammalian cells, operating downstream of Frizzled-1 through Dishevelled-1 and Dishevelled-3 (not Dvl-2), and then through RhoA, Rac1, Cdc42, and MEKK1/MEKK4 to JNK. This is distinct from the WNT-β-catenin pathway that requires both Gαo and Gαq. siRNA knockdown epistasis, Dapper1 (Dvl antagonist) expression, dominant-negative small GTPases, chemical inhibitors (SP600125, SB203580), F9 teratocarcinoma cells Journal of cell science High 18187455
2011 The oncogenic R243H mutation in Gαo renders it constitutively active by accelerating the rate of GDP-to-GTP nucleotide exchange without impairing GTPase activity or GAP sensitivity. The mechanism involves loss of an electrostatic interaction between R243 and E43 in the P-loop. Constitutively active Gαo R243H enhances Src-STAT3 signaling in NIH-3T3 cells. Limited proteolysis assays, nucleotide-binding assays, single-turnover and steady-state GTPase assays, structural analysis, Src-STAT3 signaling readouts in cells Oncogene High 21317923
2022 Three common GNAO1 encephalopathy mutations affecting Gly203, Arg209, and Glu246 accelerate GTP uptake and inactivate GTP hydrolysis by displacing Gln205, resulting in constitutive GTP binding. The mutant Gαo proteins fail to adopt the active conformation and display aberrant interactions with signaling partners. Zn2+ restores GTPase activity and cellular interactions of these mutants without affecting wild-type Gαo. Dietary zinc rescues motor function and longevity in a Drosophila GNAO1 encephalopathy model. GTP uptake/hydrolysis assays, high-throughput drug screening, Drosophila in vivo model, biochemical interaction assays Science advances High 36206333
2013 De novo mutations in GNAO1 cause epileptic encephalopathy. Mutations predicted to destabilize Gαo fold showed impaired plasma membrane localization. The Gly203Arg substitution (switch II region) impairs GTP binding and/or downstream effector activation. Gαo-mediated inhibition of calcium currents by norepinephrine was reduced in three of four mutants by electrophysiological analysis. Whole-exome sequencing, 3D structural modeling, transient expression with localization studies, electrophysiological analysis of Ca2+ current inhibition American journal of human genetics Medium 23993195
2003 Gγ13 is coexpressed with Gαo (Gαomicron), Gβ3, and Gβ4 specifically in retinal ON bipolar cells (not OFF bipolar cells), suggesting this specific heterotrimer composition participates in ON bipolar cell signal transduction. Immunohistochemistry, single-cell PCR with cDNA hybridization, transgenic GFP mouse to identify bipolar cell types, patch-clamp confirmation of ON physiology The Journal of comparative neurology Medium 12454992
1996 Gαo and Gαi2 are expressed in separate subsets of VNO sensory neurons and are both enriched in VNO microvilli (the transduction compartment), suggesting involvement in pheromone sensory transduction. Adenylyl cyclase type II is co-expressed in both subsets. Cloning, in situ hybridization, immunohistochemistry in mouse VNO The Journal of neuroscience Medium 8558259
1995 Voltage-dependent calcium channel β-subunit, in combination with α1 subunits, has a GTPase-activating effect on Gαo in rat frontal cortex membranes. Anti-β-subunit antiserum abolished (-)-BayK 8644-stimulated GTP hydrolysis by Go, and a peptide mimicking the β-subunit binding domain of the channel complex also attenuated this GTPase activation. GTPase assay in cortical membranes, antibody inhibition, peptide competition, dihydropyridine binding FEBS letters Medium 7544301
2000 Mu-opioid receptor co-immunoprecipitates with Gαo, Gαi1, and Gαi3 (and to a lesser extent Gαi2) from solubilized rat brain membranes. GTPγS treatment abolished co-immunoprecipitation, indicating the receptor associates with these G proteins in the GDP-bound (inactive) heterotrimer state. Co-immunoprecipitation from solubilized rat brain, [3H]DAMGO binding, GTPγS sensitivity Journal of neurochemistry Medium 10693938
2017 GNAO1 mutations display two distinct functional classes: loss-of-function (LOF, <90% maximal cAMP inhibition) and gain-of-function (GOF, lower EC50 for α2A adrenergic receptor-mediated cAMP inhibition). LOF mutations correlate with epileptic encephalopathy while GOF mutations (G42R, G203R, E246K) and normally-functioning mutants associate with movement disorders. Site-directed mutagenesis, Western blot for protein expression, cAMP inhibition assay in HEK-293T cells co-expressing α2A-adrenergic receptor Neurology Medium 28747448
2020 Gαo interacts with SPTAN1 (α-spectrin, another DEE-associated protein) as identified by co-immunoprecipitation and mass spectrometry. Silencing of Gnao1 attenuated neurite outgrowth and calcium-dependent signaling. GNAO1-deficient brain organoids showed reduced SPTAN1 and Ankyrin-G expression and failed to conduct synchronized firing. Co-immunoprecipitation, mass spectrometry, siRNA knockdown, iPSC-derived brain organoids, calcium imaging, neuronal activity recording FASEB journal Medium 33107105
2008 Cardiac-specific expression of constitutively active Gαo1* in transgenic mice enhances contractile function, increases L-type Ca2+ channel current density, Ca2+ transients, and cell shortening. Protein phosphatase 1 activity was reduced in Gαo* ventricles and PKA-site phosphorylation of ryanodine receptor and phospholamban was increased, suggesting Gαo* acts via protein phosphatase 1 rather than PKA/cAMP. Transgenic mouse cardiac-specific expression, in vivo cardiac function, patch-clamp electrophysiology, Ca2+ transient measurements, protein phosphatase activity assay, PKA assay, cAMP measurement American journal of physiology. Heart and circulatory physiology Medium 18192223
2002 In C. elegans, the N-terminal region of RGS protein EGL-10 determines selective inhibition of GOA-1 (Gαo) vs. EGL-30 (Gαq). The N-terminal fragment localizes to membrane where it complexes with the GGL/RGS fragment via GPB-2 (Gβ subunit), increasing the GGL/RGS fragment abundance and membrane localization. Chimera experiments showed GGL/RGS domain of either RGS can act on either Gα, with the N-terminal region determining selectivity. C. elegans transgenic chimera expression, co-immunoprecipitation, fractionation, in vivo phenotypic assays The Journal of biological chemistry Medium 12354761
2021 GNAO1 mutations at Gln52 (Gαo[Gln52Pro] and novel Gαo[Gln52Arg]) are deficient in GTP binding and hydrolysis. At the cellular level, the mutants show defective interaction with partner proteins that recognize GDP-loaded or GTP-loaded Gαo, and plasma membrane localization is strongly reduced while Golgi localization persists. Biochemical GTP binding/hydrolysis assays, cellular interaction assays, subcellular fractionation/imaging Cells Medium 34685729
2024 Pathogenic GNAO1 mutants gain neomorphic interactions with both Ric8A and Ric8B chaperones, relocalizing them from cytoplasm to Golgi. Normally, Ric8A chaperones Gαi/Gαo/Gαq/Gα12/Gα13 and Ric8B solely chaperones Gαs/Gαolf. Pathogenic mutants show abnormal GTP uptake/hydrolysis, reduced Gβγ and RGS19 interactions, and reduced plasma membrane localization. Strength of Gαo-Ric8B interaction correlates with clinical disease severity. Co-immunoprecipitation, GTP binding/hydrolysis assays, cellular localization imaging, clinical severity correlation The Journal of clinical investigation High 38874642
2022 GNAO1 G203R and G42R mutations produce strong loss-of-function defects when evaluated as homozygous CRISPR alleles in C. elegans, and also produce dominant-negative effects in heterozygous animals and transgenic overexpression. Experiments in mice confirmed dominant-negative effects of GNAO1 G42R on multiple motor behaviors. CRISPR/Cas9 knockin in C. elegans, transgenic overexpression, heterozygous allele analysis, mouse motor behavioral assays Human molecular genetics Medium 34508586
2022 C. elegans goa-1 (GNAO1 ortholog) mutants exhibit excessive neurotransmitter release (hypersensitivity to aldicarb) and hyperactive locomotion. Caffeine rescues aberrant motor function primarily through adenosine receptor antagonism. CRISPR/Cas9 knockin in C. elegans, aldicarb assay, automated locomotion analysis, pharmacological rescue with caffeine and selective A2A receptor antagonist istradefylline Human molecular genetics Medium 34622282
2021 GNAO1 knockdown reduces Gnao1 expression in the locus coeruleus of morphine-dependent mice, and antisense oligonucleotide-mediated knockdown of Gnao1 reduced naloxone-precipitated withdrawal jumping in B6 mice, establishing a functional role for Gαo in opioid physical dependence. Antisense oligonucleotide knockdown, quantitative PCR, behavioral naloxone-precipitated withdrawal assay in recombinant congenic mouse strains Neuroscience Medium 19460419
2024 Gαo negatively regulates Schwann cell differentiation and myelination in the peripheral nervous system. Schwann cell-specific Gnao1 deletion promotes SC differentiation, accelerates remyelination after nerve injury, and increases cAMP and PI3K/AKT activity. Conversely, Gnao1 overexpression in SCs impairs myelination. Schwann cell-specific conditional KO, Gnao1 overexpression transgenic mice, nerve injury/remyelination assay, cAMP measurement, PI3K/AKT signaling, RNA sequencing Acta neuropathologica communications Medium 38331815
2021 NRSF transcriptionally represses cardiac Gαo (Gnao1) expression. Increased cardiac Gαo in NRSF-knockout mice leads to increased surface sarcolemmal L-type Ca2+ channel activity, CaMKII activation, impaired Ca2+ handling, and cardiac dysfunction. Cardiac-specific Gnao1 overexpression alone is sufficient to induce cardiac dysfunction; conversely, Gnao1 knockdown ameliorated dysfunction in heart failure models. Cardiac-specific NRSF-KO mice, dominant-negative NRSF transgenic mice, Gnao1 cardiac-specific overexpression and knockdown, cardiac function measurements, L-type Ca2+ channel activity, CaMKII signaling assays Circulation research High 34875852
1995 The phenotypic differences in GDP affinity and activated conformation between Gαo and Gαi2 upon C-terminal truncation are determined by the N-terminal portion of the protein (upstream of codon 212). Chimera analysis and deletion studies identified three hydrophobic residues (positions 11-13 from C-terminus) that make contact with the N-terminal regions (start of β-strands 1 and 3) to stabilize the C-terminal α-helix and affect nucleotide binding. In vitro synthesis in rabbit reticulocyte lysate, tryptic proteolysis assay for conformation, Gαo/Gαi2 chimeras using conserved BamHI site, GDP/GTP binding assays Biochemistry Medium 7727415
2001 The C-terminal -3 position glycine residue of Gαo is critical for productive interaction with and activation by the α2A-adrenoceptor. Mutating this Gly to Glu (as in Gαs) drastically reduced agonist potency (22-150 fold) and altered agonist efficacy at the receptor, demonstrating that the C-terminal -3 position of Gαo constrains a structure favorable for receptor interaction. Site-directed mutagenesis of Gαo C-terminus, [35S]GTPγS binding assay in Sf9 cells expressing α2A-AR, pertussis toxin resistance analysis, receptor binding assays Molecular pharmacology Medium 11562427
2014 A gain-of-function knock-in mouse (Gnao1+/G184S), carrying a RGS-insensitive mutation that prevents Go GTPase turnoff by RGS proteins, develops rare seizures, increased interictal epileptiform discharges, and strain-dependent premature death. This establishes that constitutive Gαo activation (failure to turn off) contributes to seizure susceptibility. Genomic knock-in mouse, EEG recording, pentylenetetrazol kindling, genetic modifier mapping Mammalian genome Medium 24700286
2024 Leu→Pro substitutions in the N-terminal α-helix of Gαo (L13P and L23P) uniquely destabilize the N-terminal α-helix, block formation of the heterotrimeric G-protein, and disable activation by GPCRs, without affecting enzymatic activity or overall folding. This is associated with a parkinsonism phenotype distinct from the hyperkinetic movement disorder seen with other GNAO1 mutations. Structural and biochemical analysis of purified mutant proteins, heterotrimer formation assay, GPCR coupling assay, clinical phenotyping Movement disorders Medium 38358016
2023 An intronic GNAO1 mutation (c.724-8G>A) creates a novel splice acceptor site causing in-frame 6-bp intronic retention (2 amino acid insertion, Pro-Gln) within the switch III region of Gαo. This insertion misconfigures switch III, creating novel interactions with switch II, resulting in increased GTP uptake, defective GTP hydrolysis, and aberrant effector protein interactions, while Gβγ interactions and GPCR coupling remain unchanged. RNA splicing analysis from patient lymphoblastoid cells, molecular biochemical characterization (GTP uptake/hydrolysis), protein interaction assays Med (New York, N.Y.) Medium 37001522
2022 The intronic GNAO1 c.724-8G>A variant causes an in-frame 2 amino acid insertion (Thr241_Asn242insProGln) in Gαo. The mutant protein shows no significant difference in expression levels but displays partially shifted localization to the cytoplasm compared to exclusive membrane localization of wild-type Gαo. RNA extraction from patient lymphoblastoid cells, immunoblotting, immunostaining of transfected cells Neurogenetics Low 35147852
2024 siRNA-mediated depletion of Gnao1 in Neuro2a cells perturbs expression of transcripts associated with Rho GTPase signaling and impairs neurite outgrowth. The G203R variant of Gαo disables growth cone formation in iPSC-derived cortical neurons and disrupts neuro-spherical assembly and phospho-MLC2 polarity in cortical organoids. Rho kinase inhibitor Y27632 restores these morphological phenotypes, placing Gαo upstream of the Rho-ROCK pathway in neuronal morphogenesis. siRNA knockdown, iPSC-derived cortical neurons and organoids from patient with G203R variant, immunofluorescence for growth cone markers and phospho-MLC2, pharmacological rescue with Y27632 Scientific reports Medium 39048611
1998 Human substance P receptor (hSPR) directly activates Gαo (as well as Gαq/11 and Gαs) in CHO cells, as demonstrated by photoaffinity labeling of Gα subunits with [32P]AA-GTP upon hSPR stimulation followed by subunit-specific immunoprecipitation. Photoaffinity labeling with [32P]azidoanilido-GTP, subunit-specific immunoprecipitation FEBS letters Low 9654151
1989 Five pertussis toxin-sensitive G proteins were purified from bovine brain including two Gαo isoforms (Gαo-I and Gαo-II) with distinct peptide mapping profiles and migration rates. Only Gαo-I is present in NG 108-15 cell membranes. Protein purification, immunochemical characterization, in situ peptide mapping, PAGE European journal of biochemistry Medium 2506013
1996 ADP-ribosylation by pertussis toxin (IAP) of Gαo occurs at the C-terminal cysteine residue of Gαo, causing conformational changes as evidenced by enhanced immunoreactivity to C-terminal (but not N-terminal) antibodies and increased sensitivity to trypsin proteolysis. The kinetics of Gi/Go ADP-ribosylation parallel the rate of loss of coupling between inhibitory neuroreceptors and adenylyl cyclase. Cholera toxin/IAP ADP-ribosylation in pituitary cells, antibody immunoreactivity assays, trypsin proteolysis, adenylyl cyclase coupling kinetics Journal of receptor and signal transduction research Low 8897310
2021 The GNAO1 R209C mutation in ALL increases GTPase activity and promotes cell proliferation and neoplastic transformation. Combined with ETV6-RUNX1 fusion, R209C activates PI3K/Akt/mTOR signaling. mTORC1 phosphorylates p300 acetyltransferase, which acetylates ETV6-RUNX1 and enhances its transcriptional activity on the GNAO1 R209C promoter, forming a positive feedback loop. Ectopic expression in cell lines, cell proliferation assay, transformation assay, PI3K/Akt/mTOR pathway analysis, p300 phosphorylation/acetylation assays Blood Medium 32898863

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Sensory transduction in vomeronasal neurons: evidence for G alpha o, G alpha i2, and adenylyl cyclase II as major components of a pheromone signaling cascade. The Journal of neuroscience : the official journal of the Society for Neuroscience 254 8558259
2000 G alpha(i) and G alpha(o) are target proteins of reactive oxygen species. Nature 220 11100733
2013 De Novo mutations in GNAO1, encoding a Gαo subunit of heterotrimeric G proteins, cause epileptic encephalopathy. American journal of human genetics 191 23993195
2000 The light response of ON bipolar neurons requires G[alpha]o. The Journal of neuroscience : the official journal of the Society for Neuroscience 164 11124982
2011 G protein G(alpha)o is essential for vomeronasal function and aggressive behavior in mice. Proceedings of the National Academy of Sciences of the United States of America 147 21768373
1994 Muscarinic M-current inhibition via G alpha q/11 and alpha-adrenoceptor inhibition of Ca2+ current via G alpha o in rat sympathetic neurones. The Journal of physiology 130 7932231
1997 G alpha(o) is necessary for muscarinic regulation of Ca2+ channels in mouse heart. Proceedings of the National Academy of Sciences of the United States of America 113 9050846
2005 Cannabinoid receptor-induced neurite outgrowth is mediated by Rap1 activation through G(alpha)o/i-triggered proteasomal degradation of Rap1GAPII. The Journal of biological chemistry 107 15657046
2003 G protein subunit G gamma 13 is coexpressed with G alpha o, G beta 3, and G beta 4 in retinal ON bipolar cells. The Journal of comparative neurology 105 12454992
2017 Movement disorder in GNAO1 encephalopathy associated with gain-of-function mutations. Neurology 92 28747448
2005 The G alpha(o/i)-coupled cannabinoid receptor-mediated neurite outgrowth involves Rap regulation of Src and Stat3. The Journal of biological chemistry 92 16046413
2003 Functional coupling of the human dopamine D2 receptor with G alpha i1, G alpha i2, G alpha i3 and G alpha o G proteins: evidence for agonist regulation of G protein selectivity. British journal of pharmacology 75 12642378
2008 G alpha o mediates WNT-JNK signaling through dishevelled 1 and 3, RhoA family members, and MEKK 1 and 4 in mammalian cells. Journal of cell science 70 18187455
2018 Deep brain stimulation is effective in pediatric patients with GNAO1 associated severe hyperkinesia. Journal of the neurological sciences 62 30103967
2018 A mechanistic review on GNAO1-associated movement disorder. Neurobiology of disease 61 29758257
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2015 Progressive Movement Disorder in Brothers Carrying a GNAO1 Mutation Responsive to Deep Brain Stimulation. Journal of child neurology 57 26060304
2011 Molecular basis of a novel oncogenic mutation in GNAO1. Oncogene 55 21317923
2022 Highlighting the Dystonic Phenotype Related to GNAO1. Movement disorders : official journal of the Movement Disorder Society 53 35722775
2000 Immunoprecipitation of high-affinity, guanine nucleotide-sensitive, solubilized mu-opioid receptors from rat brain: coimmunoprecipitation of the G proteins G(alpha o), G(alpha i1), and G(alpha i3). Journal of neurochemistry 47 10693938
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1995 Voltage-dependent calcium channel beta-subunits in combination with alpha 1 subunits, have a GTPase activating effect to promote the hydrolysis of GTP by G alpha o in rat frontal cortex. FEBS letters 44 7544301
2022 Restoration of the GTPase activity and cellular interactions of Gαo mutants by Zn2+ in GNAO1 encephalopathy models. Science advances 42 36206333
2016 Recurrent GNAO1 Mutations Associated With Developmental Delay and a Movement Disorder. Journal of child neurology 40 27625011
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2019 Genes CEP55, FOXD3, FOXF2, GNAO1, GRIA4, and KCNA5 as potential diagnostic biomarkers in colorectal cancer. BMC medical genomics 38 30987631
1997 Role of G alpha q or G alpha o proteins in alpha 1-adrenoceptor subtype-mediated responses in Fischer 344 rat aorta. Molecular pharmacology 38 9415716
2022 Caenorhabditis elegans provides an efficient drug screening platform for GNAO1-related disorders and highlights the potential role of caffeine in controlling dyskinesia. Human molecular genetics 37 34622282
2002 An N-terminal region of Caenorhabditis elegans RGS proteins EGL-10 and EAT-16 directs inhibition of G(alpha)o versus G(alpha)q signaling. The Journal of biological chemistry 37 12354761
2014 Gain-of-function mutation in Gnao1: a murine model of epileptiform encephalopathy (EIEE17)? Mammalian genome : official journal of the International Mammalian Genome Society 35 24700286
2023 Severity of GNAO1-Related Disorder Correlates with Changes in G-Protein Function. Annals of neurology 34 37548038
2020 GNAO1 organizes the cytoskeletal remodeling and firing of developing neurons. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 34 33107105
2016 GNAO1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females. Orphanet journal of rare diseases 34 27072799
2022 Mouse models characterize GNAO1 encephalopathy as a neurodevelopmental disorder leading to motor anomalies: from a severe G203R to a milder C215Y mutation. Acta neuropathologica communications 32 35090564
2017 GNAO1-associated epileptic encephalopathy and movement disorders: c.607G>A variant represents a probable mutation hotspot with a distinct phenotype. Epileptic disorders : international epilepsy journal with videotape 32 28202424
1990 Pretreatment of mouse striatal neurons in primary culture with 17 beta-estradiol enhances the pertussis toxin-catalyzed ADP-ribosylation of G alpha o,i protein subunits. Journal of neurochemistry 32 2118945
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2019 Long-term effect of subthalamic and pallidal deep brain stimulation for status dystonicus in children with methylmalonic acidemia and GNAO1 mutation. Journal of neural transmission (Vienna, Austria : 1996) 31 31076915
2018 GNAO1 Mutation-Induced Pediatric Dystonic Storm Rescue With Pallidal Deep Brain Stimulation. Journal of child neurology 30 29661126
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2021 Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of GNAO1 and GNAI1 for the Dominant Disease. Cells 27 34685729
2015 Clinical whole-exome sequencing reveals a novel missense pathogenic variant of GNAO1 in a patient with infantile-onset epilepsy. Clinica chimica acta; international journal of clinical chemistry 27 26485252
2020 Mice with GNAO1 R209H Movement Disorder Variant Display Hyperlocomotion Alleviated by Risperidone. The Journal of pharmacology and experimental therapeutics 25 31907305
2017 A case of severe movement disorder with GNAO1 mutation responsive to topiramate. Brain & development 24 27916449
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2021 Identification of functional cooperative mutations of GNAO1 in human acute lymphoblastic leukemia. Blood 21 32898863
2001 Binding of G alpha(o) N terminus is responsible for the voltage-resistant inhibition of alpha(1A) (P/Q-type, Ca(v)2.1) Ca(2+) channels. The Journal of biological chemistry 21 11395521
2020 Humanization of Drosophila Gαo to Model GNAO1 Paediatric Encephalopathies. Biomedicines 20 33036271
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2021 Phenotypes of GNAO1 Variants in a Chinese Cohort. Frontiers in neurology 19 34122306
2009 Gnao1 (G alphaO protein) is a likely genetic contributor to variation in physical dependence on opioids in mice. Neuroscience 19 19460419
2024 Neomorphic Gαo mutations gain interaction with Ric8 proteins in GNAO1 encephalopathies. The Journal of clinical investigation 18 38874642
2024 Dyskinetic crisis in GNAO1-related disorders: clinical perspectives and management strategies. Frontiers in neurology 18 38903163
2013 The down-regulation of GNAO1 and its promoting role in hepatocellular carcinoma. Bioscience reports 18 23984917
1997 Inactivation of the G alpha i2 and G alpha o genes by homologous recombination. Receptors & channels 17 9606722
1995 Developmental expression of G alpha o and G alpha s isoforms in PC12 cells: relationship to neurite outgrowth. Brain research. Developmental brain research 17 7493405
2024 Clinical and Molecular Profiling in GNAO1 Permits Phenotype-Genotype Correlation. Movement disorders : official journal of the Movement Disorder Society 16 38881224
2023 Phenotypic Assessment of Pathogenic Variants in GNAO1 and Response to Caffeine in C. elegans Models of the Disease. Genes 16 36833246
2023 Phenotypic Diversity in GNAO1 Patients: A Comprehensive Overview of Variants and Phenotypes. Human mutation 16 40225165
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2019 Mouse models of GNAO1-associated movement disorder: Allele- and sex-specific differences in phenotypes. PloS one 14 30682176
2016 Toll-like receptor 2-mediated MAPKs and NF-κB activation requires the GNAO1-dependent pathway in human mast cells. Integrative biology : quantitative biosciences from nano to macro 14 27515449
2014 Comprehensive pathway-based analysis identifies associations of BCL2, GNAO1 and CHD2 with non-obstructive azoospermia risk. Human reproduction (Oxford, England) 14 24549219
2024 Cortical neurons obtained from patient-derived iPSCs with GNAO1 p.G203R variant show altered differentiation and functional properties. Heliyon 13 38434323
2023 In-depth molecular profiling of an intronic GNAO1 mutant as the basis for personalized high-throughput drug screening. Med (New York, N.Y.) 13 37001522
2023 Deep Brain Stimulation for GNAO1-Associated Dystonia: A Systematic Review and Meta-Analysis. Neuromodulation : journal of the International Neuromodulation Society 13 37999699
2021 NRSF-GNAO1 Pathway Contributes to the Regulation of Cardiac Ca2+ Homeostasis. Circulation research 13 34875852
2018 DNMT1 mediated promoter methylation of GNAO1 in hepatoma carcinoma cells. Gene 13 29709639
2022 Mice with monoallelic GNAO1 loss exhibit reduced inhibitory synaptic input to cerebellar Purkinje cells. Journal of neurophysiology 12 35080448
2021 Cognitive Assessment in GNAO1 Neurodevelopmental Disorder Using an Eye Tracking System. Journal of clinical medicine 12 34441836
1989 Distribution of the alpha-subunit of the guanine nucleotide-binding protein Gi2 and its comparison to G alpha o. Journal of receptor research 11 2512386
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2022 An intronic GNAO1 variant leading to in-frame insertion cause movement disorder controlled by deep brain stimulation. Neurogenetics 10 35147852
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2018 A patient with a GNAO1 mutation with decreased spontaneous movements, hypotonia, and dystonic features. Brain & development 10 29935962
2008 Enhanced calcium cycling and contractile function in transgenic hearts expressing constitutively active G alpha o* protein. American journal of physiology. Heart and circulatory physiology 10 18192223
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2024 GNAO1 Mutations Affecting the N-Terminal α-Helix of Gαo Lead to Parkinsonism. Movement disorders : official journal of the Movement Disorder Society 8 38358016
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2023 CRISPR/Cas9-generated mouse model with humanizing single-base substitution in the Gnao1 for safety studies of RNA therapeutics. Frontiers in genome editing 7 37077890
2020 BRD9 controls the oxytocin signaling pathway in gastric cancer via CANA2D4, CALML6, GNAO1, and KCNJ5. Translational cancer research 7 35117701
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2024 Personalized allele-specific antisense oligonucleotides for GNAO1-neurodevelopmental disorder. Molecular therapy. Nucleic acids 6 39897576
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1996 ADP-ribosylation of G alpha i and G alpha o in pituitary cells enhances their recognition by antibodies directed against their carboxyl termini. Journal of receptor and signal transduction research 4 8897310
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2024 GNAO1 overexpression promotes neural differentiation of glioma stem-like cells and reduces tumorigenicity through TRIM21/CREB/HES1 axis. Oncogene 3 39580518
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