Affinage

GNAO1

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

Length
354 aa
Mass
40.1 kDa
Annotated
2026-04-28
100 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GNAO1 encodes Gαo, the most abundant heterotrimeric G protein α-subunit in the mammalian nervous system, which couples diverse GPCRs to downstream effectors governing neuronal excitability, sensory transduction, neurite outgrowth, and myelination. Gαo inhibits N-type and L-type voltage-gated Ca²⁺ channels through both direct interaction with the α1A (Cav2.1) subunit and Gβγ release (PMID:7932231, PMID:11395521, PMID:9050846), is the obligate transducer of the mGluR6 cascade in retinal ON bipolar cells (PMID:11124982) and of V2R-mediated pheromone signaling in vomeronasal neurons (PMID:21768373), and drives neurite outgrowth via Rap1→Ral→Src→Stat3 and RhoA/Rac1/Cdc42 signaling downstream of cannabinoid and Wnt receptors (PMID:15657046, PMID:16046413, PMID:18187455). De novo GNAO1 mutations cause childhood-onset neurological disease: loss-of-function alleles that impair GTP binding or plasma membrane localization produce epileptic encephalopathy, whereas gain-of-function alleles with accelerated GTP uptake or resistance to RGS-mediated GTPase acceleration primarily cause hyperkinetic movement disorders, and neomorphic interactions of mutant Gαo with Ric8A/B chaperones contribute to disease dominance (PMID:23993195, PMID:28747448, PMID:36206333, PMID:38874642).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1989 Medium

    Identification of two biochemically distinct Gαo isoforms enriched in nervous tissue established Gαo as the predominant brain G protein α-subunit and raised the question of which signaling pathways it serves.

    Evidence Protein purification, peptide mapping, and immunoblot tissue survey from bovine brain

    PMID:2506013

    Open questions at the time
    • No functional assay for either isoform
    • No receptor coupling demonstrated
  2. 1994 High

    Antibody microinjection demonstrated that Gαo (not Gαq/11) mediates α-adrenoceptor inhibition of N/L-type Ca²⁺ channels in sympathetic neurons, establishing the first direct effector link for Gαo.

    Evidence Intracellular anti-Gαo antibody injection with patch-clamp recording in rat SCG neurons

    PMID:7932231

    Open questions at the time
    • Mechanism of channel inhibition (direct vs. Gβγ-mediated) not resolved
    • Receptor-Gαo coupling specificity determinants unknown
  3. 1995 High

    Structural studies showed that the C-terminal region and N-terminal β-strands of Gαo determine its unique nucleotide-binding and conformational properties, distinguishing it from Gαi2.

    Evidence In vitro chimeric Gαo/Gαi2 analysis, native proteolysis, and nucleotide binding assays

    PMID:7727415

    Open questions at the time
    • No crystal structure available at this point
    • Functional consequences of C-terminal truncation in vivo unknown
  4. 1996 Medium

    Gαo expression in a distinct subset of vomeronasal sensory neurons suggested a role in pheromone transduction via a dedicated GPCR cascade, though functional proof required later conditional knockout.

    Evidence In situ hybridization and immunohistochemistry in mouse VNO

    PMID:8558259

    Open questions at the time
    • No functional ablation of Gαo in VNO neurons
    • Specific pheromone ligands transduced by Gαo-expressing neurons not identified
  5. 1997 High

    Gαo knockout mice revealed that Gαo is required for muscarinic inhibition of L-type Ca²⁺ channels in ventricular myocytes, extending Gαo effector biology beyond neurons to the heart.

    Evidence Gαo−/− knockout mouse with whole-cell patch clamp in ventricular myocytes

    PMID:9050846

    Open questions at the time
    • Mechanism of L-type channel regulation (direct vs. indirect) not established
    • Cardiac phenotype at organ level not fully characterized
  6. 2000 High

    Three contemporaneous studies resolved key coupling questions: Gαo is the essential G protein for the mGluR6 ON-bipolar cascade (ERG b-wave abolished in knockout), is directly activated by reactive oxygen species (H₂O₂ modifies Gαo causing subunit dissociation and Gβγ-dependent ERK activation), and couples to mu-opioid receptors in brain.

    Evidence Gαo−/− mouse ERG; in vitro GTPγS binding with purified Go plus H₂O₂; co-IP from solubilized rat brain

    PMID:10693938 PMID:11100733 PMID:11124982

    Open questions at the time
    • Identity of the ROS-modified residue(s) on Gαo unknown
    • Downstream effectors of Gαo in ON bipolar cells not identified
    • Mu-opioid receptor coupling shown only by co-IP, not by reconstitution
  7. 2001 High

    The Gαo N-terminus was shown to directly bind the α1A (Cav2.1) Ca²⁺ channel subunit C-terminus, mediating voltage-resistant inhibition, while Gβγ mediates the voltage-dependent component — resolving a longstanding dual-mechanism question.

    Evidence In vitro peptide binding assay and intracellular peptide/antibody dialysis during patch-clamp recording

    PMID:11395521

    Open questions at the time
    • Structural basis of the Gαo–α1A interaction not resolved
    • Relative contribution of each mechanism in intact synapses unknown
  8. 2005 High

    Two studies delineated a neurite outgrowth signaling cascade downstream of Gαo: Gαo promotes Rap1GAPII proteasomal degradation to activate Rap1, then Rap1→Ral→Src→Stat3 and Rac1→JNK→Stat3 drive neuritogenesis.

    Evidence Co-IP, proteasomal inhibitors, siRNA, dominant-negative/constitutively-active mutant epistasis in Neuro-2A cells

    PMID:15657046 PMID:16046413

    Open questions at the time
    • Whether this cascade operates in primary neurons in vivo not confirmed
    • Direct Gαo–Rap1GAPII binding domain not mapped
  9. 2008 High

    Gαo was placed into the non-canonical Wnt-JNK/planar cell polarity pathway, coupling Wnt3a to RhoA/Rac1/Cdc42 through Dishevelled-1/3, independently of Gαq and canonical β-catenin signaling.

    Evidence Systematic epistasis with dominant-negatives, shRNA, and Rho GTPase activation assays in F9 teratocarcinoma cells

    PMID:18187455

    Open questions at the time
    • Frizzled receptor identity upstream of Gαo not defined
    • In vivo PCP phenotype in Gnao1 mutants not demonstrated
  10. 2011 High

    Conditional Gαo deletion in vomeronasal neurons abolished electrophysiological responses to V2R ligands and eliminated territorial aggression, proving Gαo is the obligate transducer for this sensory modality; separately, the oncogenic R243H mutation was shown to constitutively activate Gαo by accelerating nucleotide exchange via disruption of a conserved R243-E43 salt bridge.

    Evidence Cre-loxP conditional KO with calcium imaging and behavioral assays; in vitro GTPase/exchange assays with mutagenesis and NIH-3T3 transformation

    PMID:21317923 PMID:21768373

    Open questions at the time
    • Whether all V2R-class ligands require Gαo not tested
    • R243H oncogenic pathway in human tumors not characterized
  11. 2013 High

    De novo GNAO1 mutations were identified as a cause of epileptic encephalopathy; functional assays showed that destabilizing mutations impair plasma membrane localization while switch-II mutations impair GTP binding, both reducing Gαo-mediated Ca²⁺ channel inhibition.

    Evidence Whole-exome sequencing of affected children, transient expression with immunofluorescence and electrophysiology

    PMID:23993195

    Open questions at the time
    • Genotype-phenotype correlation across full mutational spectrum not yet systematic
    • Neuronal circuit-level mechanism of seizures not addressed
  12. 2014 High

    An RGS-insensitive Gαo knock-in (G184S) produced seizures and strain-dependent lethality, demonstrating that failure to terminate Gαo signaling suffices to cause epileptic encephalopathy.

    Evidence Genomic knock-in mouse with EEG recording and PTZ kindling

    PMID:24700286

    Open questions at the time
    • Specific RGS proteins responsible for Gαo turnoff in seizure-relevant circuits not identified
    • Whether human RGS-resistance mutations exist not established at this time
  13. 2017 High

    Systematic functional classification of 15 GNAO1 clinical variants established that loss-of-function mutations associate with epileptic encephalopathy and gain-of-function mutations with movement disorders, providing a molecular framework for genotype-phenotype correlation.

    Evidence cAMP inhibition assay with co-expressed α2A-adrenergic receptor in HEK-293T cells

    PMID:28747448

    Open questions at the time
    • cAMP is only one effector readout; other downstream pathways not tested
    • Mixed phenotype patients not fully explained
  14. 2022 High

    Biochemical dissection of encephalopathy hotspot mutations (Gly203, Arg209, Glu246) revealed accelerated GTP uptake coupled with catalytic-residue (Gln205) displacement blocking hydrolysis, and Zn²⁺ was identified as a pharmacological corrector restoring GTPase activity; in parallel, C. elegans and mouse models confirmed dominant-negative activity of multiple pathological alleles.

    Evidence In vitro GTPase/exchange assays, Drosophila rescue, CRISPR knock-in in C. elegans and mouse with behavioral assays

    PMID:34508586 PMID:36206333

    Open questions at the time
    • Zn²⁺ therapeutic window and CNS delivery not addressed
    • Dominant-negative mechanism (e.g. Gβγ sequestration vs. effector titration) not resolved
  15. 2024 High

    A comprehensive survey of >80 pathological Gαo variants uncovered neomorphic interactions with Ric8A and especially Ric8B chaperones (normally Gαs/olf-specific), which relocalize to the Golgi and correlate with disease severity — establishing chaperone sequestration as a disease-driving mechanism distinct from simple loss or gain of canonical function.

    Evidence Systematic co-IP and immunofluorescence across >80 variants

    PMID:38874642

    Open questions at the time
    • Whether Ric8B sequestration disrupts Gαs/olf signaling in patient neurons not directly tested
    • Structural basis of neomorphic Ric8B binding not determined
  16. 2024 High

    Additional 2024 studies expanded the mechanistic spectrum: N-terminal Leu→Pro mutations uniquely block heterotrimer formation and GPCR coupling (associated with parkinsonism); Gαo regulates Rho GTPase-dependent cytoskeletal remodeling in developing neurons rescuable by ROCK inhibition; and Schwann cell-expressed Gαo negatively regulates myelination via cAMP/PI3K-AKT suppression.

    Evidence Biochemical heterotrimer assays; patient iPSC-derived neurons with ROCK inhibitor rescue; SC-specific conditional KO and overexpression mice with nerve injury remyelination

    PMID:38331815 PMID:38358016 PMID:39048611

    Open questions at the time
    • Whether ROCK inhibitors have therapeutic potential for GNAO1 encephalopathy in vivo unknown
    • Receptor(s) upstream of Gαo in Schwann cells not identified
    • Parkinsonism phenotype documented in only two families

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of Gαo interactions with effectors and Ric8 chaperones, the identity of the specific neuronal circuits whose dysfunction produces seizures versus movement disorders, whether Zn²⁺ or ROCK inhibitors can be developed as therapeutics, and the in vivo relevance of the Rap1/Stat3 neurite outgrowth pathway.
  • No high-resolution structure of Gαo in complex with any effector or Ric8
  • Circuit-level mechanisms linking Gαo dysfunction to seizures vs. dyskinesia unknown
  • No clinical trial data for any GNAO1-targeted therapy

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 6 GO:0060089 molecular transducer activity 6 GO:0098772 molecular function regulator activity 5
Localization
GO:0005886 plasma membrane 4 GO:0005829 cytosol 2 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-112316 Neuronal System 6 R-HSA-1643685 Disease 6 R-HSA-9709957 Sensory Perception 4 R-HSA-1266738 Developmental Biology 3
Partners
CACNA1ADVL1DVL3GRM6RAP1GAP2RIC8ARIC8BSPTAN1
Complex memberships
Heterotrimeric Go (Gαo/Gβγ)

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Gαo and Gαi2 are expressed in distinct subsets of vomeronasal sensory neurons and are enriched in VNO microvilli, indicating roles in pheromone sensory transduction via separate G-protein-coupled cascades alongside adenylyl cyclase type II. In situ hybridization, immunohistochemistry, cDNA cloning The Journal of Neuroscience Medium 8558259
2000 H2O2 directly activates purified heterotrimeric Go (but not Gs) in vitro by modifying Gαo, leading to subunit dissociation and subsequent Gβγ-dependent ERK activation, identifying Gαo as a direct target of reactive oxygen species. In vitro [35S]GTPγS binding assay with purified proteins, cardiomyocyte cell experiments, Gβγ inhibition Nature High 11100733
2000 Gαo is required for the light response of ON bipolar neurons: mice lacking Gαo show complete absence of the b-wave of the ERG while rod/cone photocurrents (a-wave) and retinal architecture are normal, establishing Gαo as the essential G protein in the mGluR6 cascade. Knockout mouse (Gαo−/−), electroretinography The Journal of Neuroscience High 11124982
1994 Intraneuronal antibody microinjection established that Gαo (not Gαq/11) mediates α-adrenoceptor inhibition of N/L-type Ca2+ current in sympathetic neurons, while Gαq/11 mediates muscarinic inhibition of M-current. Intracellular antibody microinjection in SCG neurons, patch-clamp electrophysiology The Journal of Physiology High 7932231
1997 Gαo is required for muscarinic inhibition of L-type Ca2+ channels in ventricular myocytes; Gαo−/− mice show no muscarinic inhibition of L-type Ca2+ current while isoproterenol responses and muscarinic regulation of atrial K+ channels remain normal. Homologous recombination knockout mouse, whole-cell patch clamp in ventricular myocytes Proceedings of the National Academy of Sciences High 9050846
2005 Gαo/i directly interacts with Rap1GAPII and promotes its ubiquitination and proteasomal degradation, thereby activating Rap1 and inducing neurite outgrowth downstream of the CB1 cannabinoid receptor in Neuro-2A cells. Co-immunoprecipitation, proteasomal inhibitor (lactacystin), siRNA, dominant-negative constructs, pertussis toxin The Journal of Biological Chemistry High 15657046
2005 Gαo/i-coupled CB1 receptor sequentially activates Rap1→Ral→Src→Stat3 and also Rac1→JNK→Stat3 pathways for neurite outgrowth; Src activation requires both Rap1 and Ral downstream of Gαo. Dominant-negative and constitutively active mutant overexpression, pharmacological inhibitors, phosphorylation assays in Neuro-2A cells The Journal of Biological Chemistry High 16046413
2008 Gαo mediates WNT3a-JNK (planar cell polarity) signaling in mammalian F9 cells through Dishevelled-1 and Dishevelled-3 (but not Dvl-2), RhoA/Rac1/Cdc42, and MEKK1/MEKK4, independently of Gαq; Gαo is not required for canonical WNT-β-catenin signaling alone. Epistasis with dominant-negative/shRNA, Dapper1 antagonist, chemical inhibitors, RhoA/Rac1/Cdc42 activation assays in mouse F9 teratocarcinoma cells Journal of Cell Science High 18187455
2011 Conditional deletion of Gαo in vomeronasal sensory neurons abolishes electrophysiological and Ca2+ responses to MHC class I antigens, major urinary proteins, and N-formylated mitochondrial peptides (V2R neuron ligands), and eliminates male-male and maternal territorial aggression. Cre-loxP conditional knockout, extracellular field recordings, calcium imaging, behavioral tests Proceedings of the National Academy of Sciences High 21768373
2011 The oncogenic Gαo R243H mutation accelerates guanine nucleotide exchange (constitutive activation) without impairing GTPase activity or GAP sensitivity; the mechanism involves loss of a conserved R243-E43 electrostatic interaction in the P-loop. Constitutively active Gαo R243H enhances Src-STAT3 signaling to promote cellular transformation. Limited proteolysis, nucleotide-binding assays, single-turnover and steady-state GTPase assays, mutagenesis, NIH-3T3 transformation assay Oncogene High 21317923
2013 De novo GNAO1 mutations cause epileptic encephalopathy; mutations predicted to destabilize the Gα fold impair plasma membrane localization, while the Gly203Arg switch-II mutation impairs GTP binding/downstream effector activation. All four mutants show reduced Gαo-mediated inhibition of calcium currents by norepinephrine. Whole-exome sequencing, transient expression with immunofluorescence localization, electrophysiological calcium current recording, 3D structural modeling American Journal of Human Genetics High 23993195
2001 The N-terminus of Gαo directly binds the C-terminus of the α1A (P/Q-type, Cav2.1) Ca2+ channel subunit in vitro, and this interaction mediates voltage-resistant (but not voltage-dependent) inhibition of α1A Ca2+ currents; Gβγ mediates the voltage-dependent component. In vitro binding assay with peptides/antisera, patch-clamp electrophysiology with peptide/antibody dialysis The Journal of Biological Chemistry High 11395521
1995 Voltage-dependent Ca2+ channel β-subunits act as GTPase-activating proteins for Gαo in rat frontal cortex membranes; an anti-β-subunit antiserum and a peptide mimicking the β-subunit binding domain both abolish dihydropyridine agonist-stimulated GTP hydrolysis by Go. GTPase assay in cortical membranes, antibody and peptide inhibition, [3H]dihydropyridine binding FEBS Letters Medium 7544301
1995 The C-terminal region and amino-terminal contacts (β-strands 1 and 3) of Gαo determine its characteristic nucleotide binding and conformation properties; C-terminal truncation of 14 residues decreases GDP affinity and reveals a GTP-activated conformation in Gαo but not Gαi2, a difference mapped to hydrophobic residues 11-13 from the C-terminus. In vitro translation, native tryptic proteolysis, chimeric Gαo/Gαi2 protein analysis, nucleotide binding assays Biochemistry High 7727415
2000 Mu-opioid receptor co-immunoprecipitates with Gαo, Gαi1, and Gαi3 (but not Gαs or Gαq/11) from solubilized rat brain in a GTPγS-sensitive manner, demonstrating direct receptor-G protein coupling. Immunoprecipitation from solubilized rat brain, [3H]DAMGO binding, GTPγS competition Journal of Neurochemistry Medium 10693938
1998 Human substance P receptor directly activates Gαq/11, Gαs, and Gαo in CHO cell membranes, as shown by photoaffinity labeling of Gα subunits with [32P]AA-GTP upon receptor stimulation followed by immunoprecipitation. Photoaffinity labeling ([32P]azidoanilido-GTP), immunoprecipitation with subunit-specific antibodies FEBS Letters Medium 9654151
2003 G protein subunit Gγ13 is coexpressed with Gαo, Gβ3, and Gβ4 specifically in retinal ON bipolar cell dendrites (not OFF), identifying the specific heterotrimer (Gαo/Gβ3 or Gβ4/Gγ13) mediating ON bipolar phototransduction. Immunohistochemistry, GFP-transgenic mouse single-cell RT-PCR, patch-clamp identification Journal of Comparative Neurology Medium 12454992
2014 A gain-of-function knock-in mutation (G184S) preventing RGS-mediated GTPase acceleration in Gαo causes epileptiform discharges, seizures, and strain-dependent lethality in mice, demonstrating that constitutive Gαo activity (failure of turnoff) drives epileptic encephalopathy. Genomic knock-in mouse, EEG recording, pentylenetetrazol kindling, genetic modifier mapping Mammalian Genome High 24700286
2017 GNAO1 clinical mutations segregate into loss-of-function (reduced cAMP inhibition, associated with epileptic encephalopathy) and gain-of-function (lower EC50 for α2A-AR-mediated cAMP inhibition, including G42R, G203R, E246K; associated with movement disorders), establishing a functional correlation with clinical phenotype. Site-directed mutagenesis, HEK-293T expression, Western blot, cAMP inhibition assay with co-expressed α2A-adrenergic receptor Neurology High 28747448
2020 Co-immunoprecipitation and mass spectrometry identified SPTAN1 (α-II spectrin) as an interacting partner of Gαo; GNAO1 silencing attenuates neurite outgrowth, reduces SPTAN1 and Ankyrin-G expression in brain organoids, and impairs synchronized neuronal firing. Co-immunoprecipitation, mass spectrometry, siRNA knockdown, iPSC-derived brain organoids, calcium imaging FASEB Journal Medium 33107105
2022 The three most common encephalopathy mutations (Gly203, Arg209, Glu246) accelerate GTP uptake and inactivate GTP hydrolysis by displacing Gln205 critical for catalysis, resulting in constitutive GTP binding but failure to adopt the active conformation. Zn2+ restores GTPase activity and cellular interactions of these mutants without affecting wild-type Gαo. In vitro GTPase assay, nucleotide binding assay, protein-protein interaction assay, high-throughput drug screening, Drosophila model Science Advances High 36206333
2022 All tested GNAO1 pathological mutations (G42R, G203R, R209C) result in loss of function in C. elegans goa-1 models and also exhibit dominant-negative effects in heterozygous animals; G42R dominant-negative effects were confirmed in mice impairing motor behaviors. CRISPR/Cas9 knock-in in C. elegans and mouse, behavioral assays, transgenic overexpression Human Molecular Genetics High 34508586
2021 Gln52 mutations in Gαo (Q52P, Q52R) abolish GTP binding and hydrolysis; the mutant proteins are defective in interaction with GDP-loaded and GTP-loaded partner proteins, and show strongly reduced plasma membrane localization with accumulation at non-membrane sites. In vitro GTP binding and hydrolysis assays, co-immunoprecipitation, immunofluorescence localization in mammalian cells Cells High 34685729
2024 GNAO1 encephalopathy mutants gain aberrant neomorphic interactions with both Ric8A and Ric8B chaperones (Ric8B normally handles only Gαs/olf), relocalizing them from cytoplasm to Golgi. This neomorphic Ric8 sequestration imbalances neuronal G protein signaling networks and mediates disease dominance; the strength of Gαo-Ric8B interaction correlates with disease severity. Co-immunoprecipitation, immunofluorescence colocalization, systematic characterization of >80 pathological Gαo variants for GTP handling and partner binding The Journal of Clinical Investigation High 38874642
2021 GNAO1-encoded Gαo is transcriptionally regulated by NRSF in the heart; increased cardiac Gαo elevates L-type Ca2+ channel surface activity, activates CaMKII signaling, and impairs Ca2+ handling in ventricular myocytes, causing cardiac dysfunction. Cardiac-specific NRSF knockout mice, dominant-negative NRSF mice, cardiac-specific Gnao1 overexpression transgenic mice, Gnao1 genetic knockdown, L-type Ca2+ channel current recording Circulation Research High 34875852
2008 Cardiac-specific expression of constitutively active Gαo1* enhances L-type Ca2+ channel current density, calcium transients, and contractile function, associated with increased phosphorylation of ryanodine receptor and phospholamban via reduced protein phosphatase 1 activity (not PKA). Transgenic mice with cardiac-specific constitutively active Gαo*, whole-cell patch clamp, Ca2+ transient measurement, phosphorylation assays, PP1 activity assay American Journal of Physiology – Heart and Circulatory Physiology High 18192223
2024 Leu→Pro substitutions at positions 13 and 23 (N-terminal α-helix of Gαo) uniquely destabilize the N-terminal α-helix, blocking heterotrimeric G-protein formation and GPCR-mediated activation, without impairing GTPase activity or overall folding; clinically associated with parkinsonism phenotype. Structural and biochemical characterization of mutant Gαo proteins, heterotrimeric complex formation assay, GPCR coupling assay Movement Disorders High 38358016
2024 Gαo acts as a molecular switch regulating Rho GTPase signaling in developing neurons; GNAO1 knockdown or the G203R mutation disrupts Rho GTPase-dependent actin cytoskeleton remodeling, growth cone formation, and self-organizing neural rosette assembly; Rho kinase inhibitor Y27632 rescues these morphological phenotypes. siRNA knockdown in Neuro2a, iPSC-derived neurons and organoids from GNAO1 G203R patient, phospho-MLC2 immunostaining, ROCK inhibitor rescue Scientific Reports Medium 39048611
2002 In C. elegans, the N-terminal region of the RGS protein EGL-10 directs selective inhibition of GOA-1 (Gαo) by forming a complex with the GGL/RGS domain and its associated Gβ subunit GPB-2, affecting membrane localization and G protein target selectivity of the RGS domain. C. elegans transgenic epistasis, chimeric RGS protein analysis, co-immunoprecipitation, subcellular fractionation The Journal of Biological Chemistry Medium 12354761
2024 Gnao1 expressed in Schwann cells (not neurons) negatively regulates myelination: SC-specific Gnao1 deletion elevates cAMP and activates PI3K/AKT signaling to promote SC differentiation and accelerate re-myelination after nerve injury, while Gnao1 overexpression delays re-myelination. SC-specific Gnao1 conditional knockout and overexpression mice, nerve injury re-myelination assay, cAMP measurement, PI3K/AKT pathway analysis, RNA sequencing Acta Neuropathologica Communications High 38331815
1995 αo1 protein levels increase during NGF-induced neurite outgrowth in PC12 cells and correlate with neurite length; the αo1/αo2 ratio increases selectively during differentiation, suggesting Gαo isoform-specific involvement in neuritic extension. Western blot with isoform-specific antibodies, morphometric measurement of neurite length during NGF treatment Developmental Brain Research Low 7493405
2009 Gnao1 in the locus coeruleus contributes to physical opioid dependence: Gnao1 expression is upregulated in morphine-dependent C57BL/6 but not A/J mice, and antisense knockdown of Gnao1 reduces naloxone-precipitated withdrawal jumping in dependent B6 mice. Quantitative PCR, antisense oligodeoxynucleotide knockdown, naloxone-precipitated withdrawal behavioral assay, QTL mapping Neuroscience Medium 19460419
2023 An intronic GNAO1 c.724-8G>A mutation creates a novel splice acceptor site inserting Pro-Gln in the switch III region; this misconfigures switch III-switch II interactions, increases GTP uptake, and causes defective GTP hydrolysis and aberrant effector protein interactions, while intracellular localization, Gβγ interactions, and GPCR coupling remain unchanged. NGS diagnostics, RNA splicing analysis, in vitro GTP uptake and hydrolysis assays, protein-protein interaction assays, high-throughput drug screening Med High 37001522
2024 The P170R Gαo mutant displays 100-fold accelerated GTP uptake without loss of GTP hydrolysis (biochemically distinct from all other encephalopathy mutants); Zn2+ uniquely forces the mutant to release bound GTP rather than restoring hydrolysis. In vitro GTP uptake and hydrolysis assays, Zn2+ treatment, protein interaction assays Cells High 37887313
1989 Two Gαo subforms (Gαo-I and Gαo-II) were purified from bovine brain and shown to have distinct peptide maps and migration, with Gαo-II being the only form in NG 108-15 cell membranes; Gαo is highly enriched in nervous tissue and adrenal medulla. Protein purification, immunochemical characterization, in situ peptide mapping, tissue distribution by immunoblot European Journal of Biochemistry Medium 2506013
2022 GNAO1 G203R iPSC-derived cortical neurons show aberrant cell fate commitment, reduced early neural gene expression, increased astrocyte markers, premature and defective neuronal differentiation, lower basal intracellular Ca2+ concentration, reduced spontaneous activity frequency, and smaller responses to neurotransmitters. Patient-derived hiPSC differentiation, CRISPR-corrected isogenic controls, RNA-seq, Ca2+ imaging, electrophysiology Heliyon High 38434323
2001 The C-terminal residue at position -3 (Gly) of Gαo is essential for productive interaction with the α2A-adrenoceptor; substitution with Glu (from Gαs) converts agonist clonidine from full agonist to antagonist for GTPγS binding, demonstrating that this single C-terminal residue constrains receptor-G protein coupling specificity. C-terminal mutagenesis of Gαo, [35S]GTPγS binding assay with co-expressed α2A-adrenoceptor in Sf9 cells Molecular Pharmacology Medium 11562427

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 253 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 189 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 146 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 60 29758257
2019 Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate-binding region. Epilepsia 57 30682224
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 52 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
1998 Human substance P receptor expressed in Chinese hamster ovary cells directly activates G(alpha q/11), G(alpha s), G(alpha o). FEBS letters 44 9654151
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 41 36206333
2016 Recurrent GNAO1 Mutations Associated With Developmental Delay and a Movement Disorder. Journal of child neurology 40 27625011
1995 Interactions between the amino- and carboxyl-terminal regions of G alpha subunits: analysis of mutated G alpha o/G alpha i2 chimeras. Biochemistry 39 7727415
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 36 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
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