Affinage

GAD2

Glutamate decarboxylase 2 · UniProt Q05329

Length
585 aa
Mass
65.4 kDa
Annotated
2026-06-09
100 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GAD2 encodes GAD65, a pyridoxal-5'-phosphate (PLP)-dependent decarboxylase that synthesizes GABA and serves as the principal isoform supplying GABA for synaptic vesicle loading and inhibitory neurotransmission (PMID:17482148, PMID:33236473). The enzyme exists largely as an inactive apo form that undergoes cofactor-dependent conformational changes—coupling between the C-terminal domain, catalytic loop, and PLP-binding domain drives dimer opening and autoinactivation, and the structurally flexible C-terminal region underlies GAD65's marked autoantigenicity relative to GAD67 (PMID:18184926, PMID:24927554). Enzymatic activity is acutely upregulated by PKC-epsilon-mediated phosphorylation, an effect reversible by protein phosphatases, in contrast to PKA-mediated inhibition of GAD67 (PMID:15147202). GAD65 is targeted to membranes through a palmitoylation cycle at Cys30/Cys45 written by the palmitoyl transferase HIP14, which clears it from ER/Golgi to the trans-Golgi network and onward via a post-Golgi vesicular pathway toward presynaptic clusters; disruption of this cycle by mutant huntingtin shifts GAD65 to cytosolic diffusion (PMID:18230651, PMID:22103299). Loss of GAD65 lowers brain GABA and causes spontaneous seizures, premature lethality, and developmental defects including cleft palate and omphalocele, and epigenetic suppression of Gad2 underlies inflammatory and neuropathic pain states (PMID:33236473, PMID:25545713, PMID:21983856). GAD2 transcription is controlled by BDNF/TrkB-Ras-ERK-CREB signaling, estrogen receptor binding to promoter EREs, and HDAC- and MeCP2-mediated epigenetic regulation (PMID:20739478, PMID:19587286, PMID:21983856, PMID:26575259). Beyond the nervous system, GAD65 is the predominant islet isoform, acts as a negative regulator of glucose-stimulated insulin secretion, and is a major autoantigen whose release in exosomes and via beta-cell death drives FcR-mediated antigen presentation and T-cell activation (PMID:8243826, PMID:10950838, PMID:27872147, PMID:11016444).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1992 Medium

    Established that GAD65 is not neuron-restricted, raising the possibility of non-neurotransmission GABA functions in peripheral tissues.

    Evidence Isoform-specific Western, immunohistochemistry, and Northern blotting across peripheral tissues

    PMID:1729406

    Open questions at the time
    • No functional role for peripheral GABA defined
    • Did not address regulation of isoform-specific expression
  2. 1993 High

    Showed that GAD65 activity is more PLP-responsive than GAD67 and that the enzyme associates with vesicle-like structures, hinting at distinct cofactor regulation and membrane targeting.

    Evidence Retroviral GAD65 expression in Rat-1 fibroblasts with enzymatic assays, immunostaining, and GABA measurement; islet expression analysis by Western/IP/IHC

    PMID:8243826 PMID:8336154

    Open questions at the time
    • Molecular basis of membrane association not defined
    • PLP dependence not yet linked to a structural mechanism
  3. 1994 High

    Defined GAD2 gene structure and its conservation with GAD1, framing the two GAD genes as products of a common ancestor under independent regulation.

    Evidence Genomic cloning, structural characterization, and primer extension

    PMID:8088791

    Open questions at the time
    • Regulatory elements not functionally tested
    • Cis-elements driving cell-type specificity not mapped
  4. 1997 Medium

    Mapped the GAD65 basal promoter and a distal silencer, establishing the transcriptional control architecture distinct from GAD67.

    Evidence Primer extension and deletion reporter assays in brain and P19 cells

    PMID:9445084

    Open questions at the time
    • Trans-acting factors at the silencer not identified
    • Did not link promoter elements to physiological signaling
  5. 2000 Medium

    Demonstrated a non-neuronal physiological role: GAD65-derived GABA negatively regulates glucose-stimulated insulin secretion in beta-cells.

    Evidence RIP7-hGAD65 transgenic mouse overexpression, glucose tolerance tests, pancreas perfusion

    PMID:10950838

    Open questions at the time
    • Molecular target at/near K-ATP channel not identified
    • Loss-of-function not tested in islets
  6. 2000 Medium

    Identified an FcR-dependent route by which autoantibody-complexed GAD65 enhances antigen presentation, linking the enzyme to autoimmune T-cell activation.

    Evidence T-cell hybridoma stimulation with anti-FcR blocking antibodies

    PMID:11016444

    Open questions at the time
    • In vivo relevance to diabetes onset not established
    • APC type and FcR subtype not fully resolved
  7. 2004 High

    Resolved isoform-divergent post-translational control: PKC-epsilon phosphorylation activates GAD65 whereas PKA phosphorylation at T91 inhibits GAD67.

    Evidence In vitro kinase assays with purified proteins, [32P] incorporation, MALDI-TOF phosphosite mapping, site-directed mutagenesis

    PMID:15147202

    Open questions at the time
    • GAD65 phosphosite not pinpointed as precisely as GAD67 T91
    • Physiological stimulus driving PKC-epsilon phosphorylation not identified
  8. 2007 High

    Genetically established GAD65 as the major source of GABA for synaptic transmission and showed its vesicle anchoring does not require the N-terminus.

    Evidence GAD65 knockout mice, synaptic vesicle reconstitution with [3H]glutamate, VGAT Western blotting, truncation analysis

    PMID:17482148

    Open questions at the time
    • Vesicle anchoring determinant not mapped
    • Compensatory VGAT upregulation mechanism unresolved
  9. 2008 High

    Defined the palmitoylation cycle that traffics GAD65 from ER/Golgi to post-Golgi presynaptic vesicular compartments, and identified the C-terminal structural flexibility behind its autoantigenicity.

    Evidence FRAP and live-cell imaging with palmitoylation-deficient mutants; crystal structure with antibody epitope mapping

    PMID:18184926 PMID:18230651

    Open questions at the time
    • Palmitoyl transferase not yet identified in 2008
    • Depalmitoylation enzyme unknown
  10. 2009 High

    Defined estrogen-responsive transcriptional control of GAD2 via multiple promoter EREs and demonstrated GABAA-receptor-mediated analgesia from glial GAD65 expression.

    Evidence Luciferase reporter assays with ERE mutagenesis and ChIP in neural cells; adenoviral GAD65 delivery to satellite glia with pharmacological receptor blockade

    PMID:19587286 PMID:19656360

    Open questions at the time
    • Physiological estrogen regulation of endogenous GAD2 not shown
    • Mechanism of glial GABA release not defined
  11. 2010 High

    Identified BDNF/TrkB-Ras-ERK-CREB signaling as a cell-autonomous driver of GAD65 transcription in cortical interneurons.

    Evidence Conditional TrkB knockout, pharmacological pathway dissection, Western/qRT-PCR

    PMID:20739478

    Open questions at the time
    • Direct CREB binding to GAD2 promoter not mapped here
    • Activity-dependence of the pathway not quantified
  12. 2011 High

    Linked HDAC-mediated epigenetic suppression of Gad2 to impaired GABAergic inhibition in chronic pain, with HDAC inhibitor rescue requiring intact GAD65.

    Evidence Gad2 knockout mice, HDAC inhibitor treatment, histone-acetylation ChIP, electrophysiology, pain behavior

    PMID:21983856

    Open questions at the time
    • Specific HDAC isoform not identified in this study
    • Recruitment of HDAC to Gad2 not mechanistically defined
  13. 2012 Medium

    Identified HIP14 as the palmitoyl transferase writing GAD65 palmitoylation and showed mutant huntingtin disrupts GAD65 membrane targeting.

    Evidence Acyl-biotin exchange palmitoylation assay, subcellular fractionation, HIP14 overexpression rescue in neuronal cell lines

    PMID:22103299

    Open questions at the time
    • Single cell-line model, no in vivo confirmation
    • Functional consequence for GABA transmission not measured
  14. 2014 High

    Defined the PLP-dependent conformational mechanism of GAD65 autoinactivation and its developmental requirement in palate and abdominal wall formation.

    Evidence MD simulations, SAXS, fluorescence spectroscopy, limited proteolysis, antibody kinetics; GAD65/GAD67 double-knockout anatomical analysis

    PMID:24927554 PMID:25545713

    Open questions at the time
    • Conformational ensemble not captured at atomic resolution in apo state
    • Developmental GABA target tissues not defined
  15. 2017 High

    Showed beta-cells release GAD65 in exosomes that potently boost antigen presentation, and that orexin-activated lateral hypothalamic GAD65 neurons govern voluntary physical activity.

    Evidence Exosome isolation, liposome reconstitution, T-cell assays; optogenetics, chemogenetic silencing, and in vivo calcium recordings in GAD65-GFP mice

    PMID:27872147 PMID:28396414

    Open questions at the time
    • Trigger linking ER stress to exosomal GAD65 in vivo unresolved
    • Downstream targets of GAD65LH neurons not fully mapped
  16. 2020 High

    Demonstrated that GAD65-knockout rats recapitulate a severe seizure/lethality phenotype proportional to high GAD65 ratio and that circulating GAD65 marks real-time beta-cell destruction.

    Evidence TALEN GAD2 knockout rats with EEG, biochemistry, histology; time-resolved immunoassay in cultured beta-cells and transplant patients

    PMID:25816051 PMID:33236473

    Open questions at the time
    • Mechanism of species-dependent severity not molecularly defined
    • Clearance kinetics of plasma GAD65 not characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • How acute post-translational regulation (PKC phosphorylation, PLP cofactor cycling, HIP14 palmitoylation) is coordinated in vivo to match GABA supply to activity-dependent inhibitory demand remains unresolved.
  • No integrated in vivo model linking trafficking, cofactor state, and phosphorylation
  • Depalmitoylating enzyme for GAD65 unidentified
  • GAD65 phosphosite for PKC-epsilon not precisely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016829 lyase activity 3
Localization
GO:0005794 Golgi apparatus 2 GO:0005829 cytosol 2 GO:0031410 cytoplasmic vesicle 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-74160 Gene expression (Transcription) 3 R-HSA-112316 Neuronal System 2 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 2
Partners
HIP14VGAT

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 GAD65 and GAD67 are differentially expressed in non-neural peripheral tissues: GAD65 is specifically expressed in oviduct mucosal epithelial cells, while GAD67 is expressed in testicular spermatocytes/spermatids, demonstrating that GAD is not limited to neurons and GABA may have non-neurotransmission functions. Western blotting, immunoreactivity, Northern blotting with isoform-specific cDNA and antibody probes Journal of neurochemistry Medium 1729406
1993 GAD65 expressed in engineered Rat-1 fibroblasts via retroviral vector produces enzymatic activity more responsive to added pyridoxal phosphate (PLP) than GAD67, and GAD65 immunostaining associates with surfaces of large vesicle-like structures; cells expressing either isoform synthesize and release GABA. Retroviral cDNA expression, GAD enzymatic activity assay, immunostaining, GABA measurement Journal of neurochemistry Medium 8336154
1993 Human islets express only GAD65 (not GAD67), while rat islets predominantly express GAD65, and mouse islets express both isoforms but at severalfold lower levels; human and rat islet GAD65 exists in both membrane-bound and soluble forms. Western blotting, immunoprecipitation, immunohistochemistry using isoform-specific antibodies and monoclonal autoantibodies Diabetes High 8243826
1994 The GAD2 gene encoding GAD65 consists of 16 exons spanning more than 79 kb; transcription begins at a GC-rich TATA-less region; the exon-intron organization is largely conserved with GAD1 (GAD67) except at exons 1-3, suggesting both genes derive from a common ancestral GAD. Genomic cloning and characterization, primer extension assays Genomics High 8088791
1997 The GAD65 basal promoter maps between -740 and -60 upstream of the ATG; transcription initiates at -228 in brain and P19 cells (and -280 in brain, -360 in P19 cells); a silencer element between -1652 and -1420 represses transcription from a heterologous promoter; GAD65 and GAD67 promoters share little sequence identity consistent with independent regulation. Primer extension assays, transient transfection reporter assays, deletion analysis Developmental neuroscience Medium 9445084
2000 Increased expression of GAD65 in transgenic mouse pancreatic beta-cells elevates GABA levels and impairs first-phase insulin secretion in response to glucose, affecting a step proximal to or at the K-ATP channel, establishing GAD65-derived GABA as a negative regulator of insulin secretion. Transgenic mouse overexpression (RIP7-hGAD65), in vivo glucose tolerance tests, pancreas perfusion experiments American journal of physiology. Endocrinology and metabolism Medium 10950838
2000 GAD65 autoantibodies enhance presentation of the immunodominant GAD65 274-286 epitope to T cells via Fc receptor-mediated uptake; enhancement is inhibited by anti-FcR monoclonal antibodies, demonstrating that antibody-complexed GAD65 is taken up by antigen-presenting cells through FcR. T-cell hybridoma stimulation assay, Fc receptor blocking with monoclonal antibodies, antigen presentation assay Diabetes Medium 11016444
2004 Phosphorylation of GAD65 by protein kinase C epsilon activates GAD65 enzymatic activity; this effect is reversible by protein phosphatases. In contrast, GAD67 is inhibited by PKA-mediated phosphorylation at threonine 91 (T91), confirmed by site-directed mutagenesis (T91A abolishes phosphorylation and inhibition; T91D/E mimics phosphorylation effect). In vitro kinase assay with purified recombinant proteins, [32P]ATP incorporation, anti-phosphoserine/threonine immunoblotting, MALDI-TOF phosphosite identification, site-directed mutagenesis Biochemistry High 15147202
2007 In GAD65 knockout mice, synaptic vesicles lacking GAD65 show upregulated VGAT expression and more efficiently transport cytosolic GABA into vesicles; both full-length and N-terminally truncated GAD65 bind to GABAergic synaptic vesicles, indicating the N-terminus is not required for vesicle anchoring; GAD65 plays a major role in GABA synthesis for synaptic transmission under normal physiological conditions. GAD65 knockout mouse studies, synaptic vesicle reconstitution assay with [3H]glutamate, Western blotting for VGAT Brain research High 17482148
2008 GAD65 undergoes a palmitoylation cycle: prior to palmitoylation, GAD65 anchors to both ER and Golgi membranes; palmitoylation at Cys30 and Cys45 clears GAD65 from ER-Golgi and targets it to the trans-Golgi network and then to post-Golgi vesicular pathway toward presynaptic clusters. FRAP analysis identifies a rapid non-palmitoylated pool exchanging between cytosol and ER/Golgi, and a slow palmitoylation-competent pool replenishing Golgi via a non-vesicular depalmitoylation-repalmitoylation cycle. FRAP (fluorescence recovery after photobleaching), live-cell imaging of GAD65-GFP, palmitoylation-deficient mutant analysis Journal of cell science High 18230651
2008 Crystal structure analysis of GAD65 reveals that B-cell autoepitopes cluster in two regions (ctc1 and ctc2) at the COOH-terminal domain; the C-terminal domain of GAD65 is structurally more flexible than the equivalent region in GAD67, and T-cell epitopes co-localize with B-cell epitope clusters on solvent-exposed surfaces; this structural flexibility likely explains GAD65's greater autoantigenicity compared to GAD67. Crystal structure analysis, mutagenesis-based epitope mapping with 11 human monoclonal antibodies, cross-inhibition radioimmunoprecipitation with recombinant Fab Diabetes High 18184926
2009 The GAD2 (gad2) promoter contains three functional estrogen response elements (EREs): an ERE at -711 is essential for transactivation in both MCF-7 and neural cells; an ERE at -546 enhances transcription specifically in neural cells; an ERE at -1958 is inactive in neural cells but represses transcription in MCF-7 cells. Estradiol activates gad2 transcription via either ERalpha or ERbeta through a CREB-independent mechanism; ChIP confirms ERalpha binding to a DNA fragment containing the -546 and -711 EREs in mouse GABAergic N42 cells. Dual luciferase reporter assays, site-directed mutagenesis of EREs, chromatin immunoprecipitation (ChIP) The Journal of neuroscience High 19587286
2010 BDNF/TrkB signaling controls GAD65 transcription in a cell-autonomous manner in cortical interneurons via a Ras-ERK-CREB-dependent pathway; conditional ablation of TrkB in cortical interneurons causes decreased synaptically enriched GAD65 protein and mRNA levels. Conditional TrkB knockout in cortical interneurons, pharmacological pathway dissection (Ras-ERK-CREB), Western blotting, qRT-PCR Cerebral cortex High 20739478
2011 Persistent inflammatory and neuropathic pain epigenetically suppresses Gad2 (GAD65) transcription in rat brainstem nucleus raphe magnus through HDAC-mediated histone hypoacetylation, reducing GAD65 protein and impairing GABA synaptic inhibition; Gad2 knockout mice show sensitized pain behavior and impaired GABA synaptic function; HDAC inhibitors restore GAD65 activity and GABA synaptic function only in wild-type, not Gad2 knockout mice. Gad2 knockout mice, HDAC inhibitor treatment, chromatin immunoprecipitation for histone acetylation, electrophysiological recording of GABA synaptic function, behavioral pain assays Nature medicine High 21983856
2012 Mutant huntingtin (mhtt) impairs GAD65 palmitoylation and disrupts its subcellular localization: GAD65 shifts from Golgi membrane association to cytosolic diffusion in cells expressing mhtt; overexpression of HIP14 (the palmitoyl transferase responsible for GAD65 palmitoylation in vivo) rescues both GAD65 palmitoylation and vesicle-associated GAD65 trafficking, establishing HIP14 as the writer of GAD65 palmitoylation. Neuronal cell lines expressing normal or mutant huntingtin, acyl-biotin exchange palmitoylation assay, subcellular fractionation, HIP14 overexpression rescue The Biochemical journal Medium 22103299
2014 GAD65 undergoes cofactor (PLP)-dependent conformational changes: molecular dynamics simulations reveal coupling between the C-terminal domain, catalytic loop, and PLP-binding domain that drives structural rearrangement, dimer opening, and autoinactivation of GAD65 into an apo form; small-angle X-ray scattering and fluorescence spectroscopy confirm that apoGAD65 exists as a conformational ensemble; antibody-binding kinetics show mutually induced conformational changes, implicating GAD65 structural flexibility in its autoantigenicity. Molecular dynamics simulations, small-angle X-ray scattering (SAXS), fluorescence spectroscopy, limited proteolysis, antibody-binding kinetics Proceedings of the National Academy of Sciences of the United States of America High 24927554
2015 Prenatal immune activation (poly I:C maternal injection) increases 5-methylcytosine (5mC) levels at the GAD2 promoter region in offspring prefrontal cortex, with elevated MeCP2 binding at the GAD2 promoter, resulting in reduced GAD65 mRNA expression. Bisulfite sequencing/methylation analysis, chromatin immunoprecipitation (MeCP2), qRT-PCR in mouse model Epigenetics Medium 26575259
2016 Pancreatic islet beta cells release GAD65 (along with IA-2 and proinsulin) in exosomes; anchoring of GAD65 to exosome-mimetic liposomes strongly boosts antigen presentation and T-cell activation in the context of HLA-DR4; cytokine-induced ER stress enhances exosome secretion and promotes exosomal release of immunostimulatory chaperones (calreticulin, Gp96, ORP150). Exosome isolation from rat and human islets, electron microscopy, Western blotting, exosome-mimetic liposome reconstitution, T-cell activation assays Diabetes Medium 27872147
2017 Orexin cell activation rapidly recruits GAD65-expressing lateral hypothalamic (GAD65LH) neurons; internally initiated GAD65LH cell bursts precede and accompany spontaneous running bouts; selective chemogenetic silencing of GAD65LH neurons depresses voluntary locomotion; GAD65LH cell overactivation leads to hyperlocomotion, establishing this orexin-activated GAD65LH submodule as a governor of physical activity. Optogenetic circuit analysis, chemogenetic (DREADD) silencing, deep-brain calcium recordings in behaving GAD65-GFP mice Proceedings of the National Academy of Sciences of the United States of America High 28396414
2019 HDAC2 knockdown in rat spinal cord via lentiviral shRNA alleviates mechanical and thermal hyperalgesia after chronic constriction injury and increases GAD65 and KCC2 expression in the spinal cord, identifying GAD65 as a downstream target of HDAC2 in pain modulation. Lentiviral HDAC2 shRNA knockdown, Western blotting for GAD65 and KCC2, behavioral pain assays Frontiers in neuroscience Medium 31024248
2020 GAD65 is rapidly released from cultured human beta-cells proportional to cell death within 4-24 hours of acute insult, and is detectable in plasma within 24 hours after intraportal islet transplantation in proportion to the number of implanted beta-cells, establishing GAD65 as a real-time marker of beta-cell destruction. Time-resolved fluorescence immunoassay for GAD65, in vitro beta-cell toxin treatment, clinical intraportal transplantation study The Journal of clinical endocrinology and metabolism Medium 25816051
2020 GAD65-knockout rats (generated by TALEN) have undetectable brain GAD65 protein, significantly lower brain GABA content, exhibit spontaneous seizures and paroxysmal EEG discharge at postnatal weeks 3-4, and suffer >80% premature lethality by postnatal days 17-23, demonstrating that GAD65-derived GABA is essential for suppression of epilepsy and survival, with a more severe phenotype in rats than mice reflecting the higher GAD65/GAD67 ratio in rat (and human) brain. TALEN-based GAD2 knockout in rats, Western blotting, immunohistochemistry, GABA quantification, EEG recording, behavioral observation FASEB journal High 33236473
2014 GAD65/GAD67 double-knockout mice exhibit 100% incidence of cleft palate and omphalocele (compared to 65.8%/58.9% in GAD67-KO alone), with intermediate severity between GAD67-KO and VGAT-KO mice, demonstrating that GAD65-mediated GABAergic transmission contributes to both palate and abdominal wall formation during development. GAD65/GAD67 double knockout mice, anatomical analysis of palate elevation and omphalocele, comparison across genetic knockout lines Neuroscience Medium 25545713
2009 Adenoviral delivery of GAD65 gene into trigeminal ganglion satellite glial cells leads to GAD65 expression and GABA synthesis predominantly in SGCs; the resulting analgesic effect in the orofacial formalin test is blocked by the selective GABAA receptor antagonist bicuculline but not by GABAB antagonist CGP46381, demonstrating that GAD65-derived GABA acts on neuronal GABAA receptors to reduce pain. Adenoviral gene delivery (AdGAD65), immunohistochemistry, pharmacological receptor blockade, behavioral orofacial formalin pain test Molecular pain Medium 19656360
2003 The GAD2 promoter SNP -243 A>G increases GAD2 promoter activity approximately 6-fold in the murine insulinoma cell line betaTC3 and induces a 6-fold higher affinity for nuclear extracts, providing a functional mechanism by which this variant could alter GAD65 expression. Reporter gene (luciferase) assay in betaTC3 cells, nuclear extract binding/electrophoretic mobility shift assay PLoS biology Medium 14691540
2012 LHA GAD65 neurons are intrinsically depolarized and fire action potentials spontaneously (unlike cortical GABAergic interneurons); they fall into four electrophysiological subtypes (fast spiking, late spiking, low threshold spiking, regular spiking); approximately 40% are directly inhibited by physiological increases in extracellular glucose; they do not express MCH or orexin/hypocretin peptides. Whole-cell patch-clamp in acute brain slices of GAD65-GFP transgenic mice, 3D biocytin morphological reconstruction, glucose perfusion experiments, immunohistochemistry The Journal of physiology High 23184514

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. The New England journal of medicine 254 22296077
2004 Preferential origin and layer destination of GAD65-GFP cortical interneurons. Cerebral cortex (New York, N.Y. : 1991) 241 15115742
2011 Epigenetic suppression of GAD65 expression mediates persistent pain. Nature medicine 227 21983856
1995 Radioimmunoassays for glutamic acid decarboxylase (GAD65) and GAD65 autoantibodies using 35S or 3H recombinant human ligands. Journal of immunological methods 184 7561152
1993 Differential expression of GAD65 and GAD67 in human, rat, and mouse pancreatic islets. Diabetes 177 8243826
2020 Neurologic syndromes related to anti-GAD65: Clinical and serologic response to treatment. Neurology(R) neuroimmunology & neuroinflammation 170 32123047
2016 Primary Human and Rat β-Cells Release the Intracellular Autoantigens GAD65, IA-2, and Proinsulin in Exosomes Together With Cytokine-Induced Enhancers of Immunity. Diabetes 168 27872147
1999 Up-regulation of GAD65 and GAD67 in remaining hippocampal GABA neurons in a model of temporal lobe epilepsy. The Journal of comparative neurology 142 10441235
2015 Maternal immune activation induces GAD1 and GAD2 promoter remodeling in the offspring prefrontal cortex. Epigenetics 109 26575259
2003 GAD2 on chromosome 10p12 is a candidate gene for human obesity. PLoS biology 98 14691540
1992 Glutamate decarboxylases in nonneural cells of rat testis and oviduct: differential expression of GAD65 and GAD67. Journal of neurochemistry 92 1729406
2010 CREB-Dependent Regulation of GAD65 Transcription by BDNF/TrkB in Cortical Interneurons. Cerebral cortex (New York, N.Y. : 1991) 83 20739478
1997 Combined analysis and single-step detection of GAD65 and IA2 autoantibodies in IDDM can replace the histochemical islet cell antibody test. Diabetes 77 9075795
1997 Associations of GAD65- and IA-2- autoantibodies with genetic risk markers in new-onset IDDM patients and their siblings. The Belgian Diabetes Registry. Diabetes care 74 9314633
2005 Comparative study of GAD65-specific CD4+ T cells in healthy and type 1 diabetic subjects. Journal of autoimmunity 73 16249070
2001 Molecular mimicry in type 1 diabetes mellitus revisited: T-cell clones to GAD65 peptides with sequence homology to Coxsackie or proinsulin peptides do not crossreact with homologous counterpart. Human immunology 72 11295462
1994 The exon-intron organization of the genes (GAD1 and GAD2) encoding two human glutamate decarboxylases (GAD67 and GAD65) suggests that they derive from a common ancestral GAD. Genomics 68 8088791
2017 Orexin-driven GAD65 network of the lateral hypothalamus sets physical activity in mice. Proceedings of the National Academy of Sciences of the United States of America 66 28396414
2000 GAD65-specific autoantibodies enhance the presentation of an immunodominant T-cell epitope from GAD65. Diabetes 66 11016444
2000 Antibodies to IA-2 and GAD65 in type 1 and type 2 diabetes: isotype restriction and polyclonality. Diabetes care 63 10868836
2000 Increased expression of GAD65 and GABA in pancreatic beta-cells impairs first-phase insulin secretion. American journal of physiology. Endocrinology and metabolism 63 10950838
2001 Characterization of preparations of GAD65, proinsulin, and the islet tyrosine phosphatase IA-2 for use in detection of autoreactive T-cells in type 1 diabetes: report of phase II of the Second International Immunology of Diabetes Society Workshop for Standardization of T-cell assays in type 1 diabetes. Diabetes 59 11473034
1998 Combined analysis of GAD65 and ICA512(IA-2) autoantibodies in organ and non-organ-specific autoimmune diseases confers high specificity for insulin-dependent diabetes mellitus. Journal of autoimmunity 59 9480718
2013 GAD65, GAD67, and GABAT immunostaining in human brain and apparent GAD65 loss in Alzheimer's disease. Journal of Alzheimer's disease : JAD 55 23114513
2012 Lateral hypothalamic GAD65 neurons are spontaneously firing and distinct from orexin- and melanin-concentrating hormone neurons. The Journal of physiology 55 23184514
2008 A palmitoylation cycle dynamically regulates partitioning of the GABA-synthesizing enzyme GAD65 between ER-Golgi and post-Golgi membranes. Journal of cell science 52 18230651
2007 Role of glutamate decarboxylase (GAD) isoform, GAD65, in GABA synthesis and transport into synaptic vesicles-Evidence from GAD65-knockout mice studies. Brain research 52 17482148
2015 The GAD65 knock out mouse - a model for GABAergic processes in fear- and stress-induced psychopathology. Genes, brain, and behavior 51 25470336
2015 High diversity in the TCR repertoire of GAD65 autoantigen-specific human CD4+ T cells. Journal of immunology (Baltimore, Md. : 1950) 51 25681349
1996 Antibody cross-reactivity induced by the homologous regions in glutamic acid decarboxylase (GAD65) and 2C protein of coxsackievirus B4. Childhood Diabetes in Finland Study Group. Clinical and experimental immunology 50 9099922
2011 GAD65 autoantibodies and its role as biomarker of Type 1 diabetes and Latent Autoimmune Diabetes in Adults (LADA). Drugs of the future 49 22869930
2009 The gad2 promoter is a transcriptional target of estrogen receptor (ER)alpha and ER beta: a unifying hypothesis to explain diverse effects of estradiol. The Journal of neuroscience : the official journal of the Society for Neuroscience 49 19587286
2004 Protein phosphorylation of human brain glutamic acid decarboxylase (GAD)65 and GAD67 and its physiological implications. Biochemistry 49 15147202
1998 Are GAD65 and GAD67 associated with specific pools of GABA in brain? Perspectives on developmental neurobiology 48 9777630
2016 Garcinol Upregulates GABAA and GAD65 Expression, Modulates BDNF-TrkB Pathway to Reduce Seizures in Pentylenetetrazole (PTZ)-Induced Epilepsy. Medical science monitor : international medical journal of experimental and clinical research 47 27855137
1994 Glutamic acid decarboxylase (GAD65) autoantibodies in prediction of beta-cell function and remission in recent-onset IDDM after cyclosporin treatment. The Canadian-European Randomized Control Trial Group. Diabetes 46 7926302
2009 Adenovector GAD65 gene delivery into the rat trigeminal ganglion produces orofacial analgesia. Molecular pain 45 19656360
1997 Expression of two forms of glutamic acid decarboxylase (GAD67 and GAD65) during postnatal development of the cat visual cortex. Brain research. Developmental brain research 45 9427477
2012 Presence of GAD65 autoantibodies in the serum of children with autism or ADHD. European child & adolescent psychiatry 44 22323074
2008 Immunohistochemical localization of GABA, GAD65, and the receptor subunits GABAAalpha1 and GABAB1 in the zebrafish cerebellum. Cerebellum (London, England) 44 18633686
1999 GAD65-Reactive T cells in a non-diabetic stiff-man syndrome patient. Journal of autoimmunity 44 10330300
1998 Expression of two forms of glutamic acid decarboxylase (GAD67 and GAD65) during postnatal development of rat somatosensory barrel cortex. The Journal of comparative neurology 40 9831046
2008 Autoantibodies to GAD65 and IA-2 in canine diabetes mellitus. Veterinary immunology and immunopathology 39 18706702
2002 Induction of autoimmune diabetes through insulin (but not GAD65) DNA vaccination in nonobese diabetic and in RIP-B7.1 mice. Diabetes 39 12401715
2005 Visualization of stress-responsive inhibitory circuits in the GAD65-eGFP transgenic mice. Neuroscience letters 38 15854751
1998 Widespread expression of an autoantigen-GAD65 transgene does not tolerize non-obese diabetic mice and can exacerbate disease. Proceedings of the National Academy of Sciences of the United States of America 38 9707599
2008 COOH-terminal clustering of autoantibody and T-cell determinants on the structure of GAD65 provide insights into the molecular basis of autoreactivity. Diabetes 37 18184926
2005 Lack of support for the association between GAD2 polymorphisms and severe human obesity. PLoS biology 37 16122350
2001 Expression of GAD65 and islet cell antibody (ICA512) autoantibodies among cytoplasmic ICA+ relatives is associated with eligibility for the Diabetes Prevention Trial-Type 1. Diabetes 37 11473032
1994 Transient increase in expression of GAD65 and GAD67 mRNAs during postnatal development of rat spinal cord. The Journal of comparative neurology 37 7962709
2014 Cofactor-dependent conformational heterogeneity of GAD65 and its role in autoimmunity and neurotransmitter homeostasis. Proceedings of the National Academy of Sciences of the United States of America 36 24927554
2020 GAD2 Expression Defines a Class of Excitatory Lateral Habenula Neurons in Mice that Project to the Raphe and Pontine Tegmentum. eNeuro 35 32332079
2013 Genetic manipulation of the γ-aminobutyric acid (GABA) shunt in rice: overexpression of truncated glutamate decarboxylase (GAD2) and knockdown of γ-aminobutyric acid transaminase (GABA-T) lead to sustained and high levels of GABA accumulation in rice kernels. Plant biotechnology journal 35 23421475
2014 GAD65 haplodeficiency conveys resilience in animal models of stress-induced psychopathology. Frontiers in behavioral neuroscience 34 25147515
2009 Polymorphisms in the GAD2 gene-region are associated with susceptibility for unipolar depression and with a risk factor for anxiety disorders. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 34 19229853
2009 Genetic-induced variations in the GAD65 T-cell repertoire governs efficacy of anti-CD3/GAD65 combination therapy in new-onset type 1 diabetes. Molecular therapy : the journal of the American Society of Gene Therapy 34 19690518
1998 Elevation of brain GABA levels with vigabatrin (gamma-vinylGABA) differentially affects GAD65 and GAD67 expression in various regions of rat brain. Journal of neuroscience research 33 9669322
1999 CD4+ and CD8+ T-cell clones from congenital rubella syndrome patients with IDDM recognize overlapping GAD65 protein epitopes. Implications for HLA class I and II allelic linkage to disease susceptibility. Human immunology 31 10439311
2014 GAD65/GAD67 double knockout mice exhibit intermediate severity in both cleft palate and omphalocele compared with GAD67 knockout and VGAT knockout mice. Neuroscience 30 25545713
2012 Transcriptional control of Gad2. Transcription 30 22414751
2005 Is glutamate decarboxylase 2 (GAD2) a genetic link between low birth weight and subsequent development of obesity in children? The Journal of clinical endocrinology and metabolism 30 15671113
2005 Expression of GAD65 and GAD67 immunoreactivity in MPTP-treated monkeys with or without L-DOPA administration. Neurobiology of disease 30 15882945
2019 Normalizing HDAC2 Levels in the Spinal Cord Alleviates Thermal and Mechanical Hyperalgesia After Peripheral Nerve Injury and Promotes GAD65 and KCC2 Expression. Frontiers in neuroscience 28 31024248
1994 Autoantibodies against GAD65 rather than GAD67 precede the onset of type 1 diabetes. Autoimmunity 27 7772705
2018 Swimming Training Attenuates Allodynia and Hyperalgesia Induced by Peripheral Nerve Injury in an Adult Male Rat Neuropathic Model: Effects on Irisin and GAD65. Pain medicine (Malden, Mass.) 26 29315430
2016 Vaccination with a co-expression DNA plasmid containing GAD65 fragment gene and IL-10 gene induces regulatory CD4(+) T cells that prevent experimental autoimmune diabetes. Diabetes/metabolism research and reviews 26 26797873
2005 Sensitive non-isotopic assays for autoantibodies to IA-2 and to a combination of both IA-2 and GAD65. Clinica chimica acta; international journal of clinical chemistry 25 15963796
2004 HLA-DQ-regulated T-cell responses to islet cell autoantigens insulin and GAD65. Diabetes 25 15220192
2010 Comparison of radioimmunoprecipitation with luciferase immunoprecipitation for autoantibodies to GAD65 and IA-2beta. Diabetes care 24 20086252
2018 Enhanced susceptibility to stress and seizures in GAD65 deficient mice. PloS one 23 29377906
2016 GAD2 Alternative Transcripts in the Human Prefrontal Cortex, and in Schizophrenia and Affective Disorders. PloS one 23 26848839
2007 Visualization of two distinct classes of neurons by gad2 and zic1 promoter/enhancer elements in the dorsal hindbrain of developing zebrafish reveals neuronal connectivity related to the auditory and lateral line systems. Developmental dynamics : an official publication of the American Association of Anatomists 23 17279576
1996 Peripheral T cell clones from NOD mice specific for GAD65 peptides: lack of islet responsiveness or diabetogenicity. Journal of autoimmunity 23 8816971
2012 Palmitoylation and trafficking of GAD65 are impaired in a cellular model of Huntington's disease. The Biochemical journal 22 22103299
1997 Multiple elements regulate GAD65 transcription. Developmental neuroscience 21 9445084
2016 Anti-GAD65 Containing Cerebrospinal Fluid Does not Alter GABAergic Transmission. Frontiers in cellular neuroscience 20 27242441
2015 Plasma GAD65, a Marker for Early β-Cell Loss After Intraportal Islet Cell Transplantation in Diabetic Patients. The Journal of clinical endocrinology and metabolism 20 25816051
2013 Immunoreactivity for GABA, GAD65, GAD67 and Bestrophin-1 in the meninges and the choroid plexus: implications for non-neuronal sources for GABA in the developing mouse brain. PloS one 20 23437266
2010 Mice lacking Gad2 show altered behavioral effects of ethanol, flurazepam and gabaxadol. Addiction biology 20 20002022
2007 Mutation screen of the GAD2 gene and association study of alcoholism in three populations. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 20 17034009
1993 Rat-1 fibroblasts engineered with GAD65 and GAD67 cDNAs in retroviral vectors produce and release GABA. Journal of neurochemistry 20 8336154
2023 Cenobamate and Clobazam Combination as Personalized Medicine in Autoimmune-Associated Epilepsy With Anti-Gad65 Antibodies. Neurology(R) neuroimmunology & neuroinflammation 19 37607753
2020 AAV-Mediated Combination Gene Therapy for Neuropathic Pain: GAD65, GDNF, and IL-10. Molecular therapy. Methods & clinical development 19 32728596
2008 GAD65 as a prototypic autoantigen. Journal of autoimmunity 19 18514483
2021 Heterogeneous GAD65 Expression in Subtypes of GABAergic Neurons Across Layers of the Cerebral Cortex and Hippocampus. Frontiers in behavioral neuroscience 18 34803625
2019 Exercise training increases GAD65 expression, restores the depressed GABAA receptor function within the PVN and reduces sympathetic modulation in hypertension. Physiological reports 18 31264387
2006 Significant linkage of BMI to chromosome 10p in the U.K. population and evaluation of GAD2 as a positional candidate. Diabetes 18 16731858
1997 Combined measurements of GAD65 and ICA512 antibodies in acute onset and slowly progressive IDDM. Diabetes research and clinical practice 18 9179463
2020 Rats deficient in the GAD65 isoform exhibit epilepsy and premature lethality. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 17 33236473
2009 GAD2 gene sequence variations are associated with eating behaviors and weight gain in women from the Quebec family study. Physiology & behavior 17 19686769
2008 GAD65 IgG autoantibodies in stiff person syndrome: clonality, avidity and persistence. European journal of neurology 17 18637036
2018 An analytical comparison of three immunoassay platforms for subpicomolar detection of protein biomarker GAD65. PloS one 16 29518118
2018 GAD65 Promoter Polymorphism rs2236418 Modulates Harm Avoidance in Women via Inhibition/Excitation Balance in the Rostral ACC. The Journal of neuroscience : the official journal of the Society for Neuroscience 16 29724796
2003 T-cell function in anti-GAD65(+)diabetes with residual beta-cell function. Journal of autoimmunity 16 12604315
2002 A comprehensive, statistically powered analysis of GAD2 in type 1 diabetes. Diabetes 16 12196483
2022 Similarities between bacterial GAD and human GAD65: Implications in gut mediated autoimmune type 1 diabetes. PloS one 15 35196314
2012 Combinational spinal GAD65 gene delivery and systemic GABA-mimetic treatment for modulation of spasticity. PloS one 15 22291989
1997 Highly-sensitive and specific enzyme-linked immunosorbent assays for GAD65 autoantibodies using a thioredoxin-GAD65 fusion antigen. Journal of immunological methods 15 9368643
2021 Spinal GABAergic neurons are under feed-forward inhibitory control driven by Aδ and C fibers in Gad2 td-Tomato mice. Molecular pain 14 33586515
2019 Combined Analysis of GAD65, miR-375, and Unmethylated Insulin DNA Following Islet Transplantation in Patients With T1D. The Journal of clinical endocrinology and metabolism 14 30203041

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