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Gene Review

Gad2  -  glutamic acid decarboxylase 2

Mus musculus

Synonyms: 6330404F12Rik, 65 kDa glutamic acid decarboxylase, GAD(65), GAD-65, GAD65, ...
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Disease relevance of Gad2


Psychiatry related information on Gad2

  • Targeted disruption of tPA release or its upstream regulation by glutamic acid decarboxylase (GAD65) prevented MD-induced spine loss that was pharmacologically rescued concomitant with critical period plasticity [6].
  • Recently we have produced GAD65 -/- mice and demonstrated that lack of GAD65 does not change brain GABA contents or animal behavior, except for a slight increase in susceptibility to seizures [7].

High impact information on Gad2

  • Short-term presynaptic dynamics reflected a synaptic reorganization in GAD65 knockout mice after chronic diazepam treatment [8].
  • In mice of all ages lacking an isoform of GABA (gamma-aminobutyric acid) synthetic enzyme (GAD65), as well as in immature wild-type animals before the onset of their natural critical period, benzodiazepines selectively reduced a prolonged discharge phenotype to unmask plasticity [8].
  • Furthermore, NOD mice receiving intrathymic injections of GAD65 exhibit markedly reduced T-cell proliferative responses to GAD and to the rest of the panel, in addition to remaining free of diabetes [9].
  • Finally, GAD65 peptide treatment reduced insulitis and long-term IDDM incidence [10].
  • We previously demonstrated that a spontaneous Th1 response against glutamate decarboxylase (GAD65) arises in NOD mice at four weeks in age and subsequently T cell autoimmunity spreads both intramolecularly and intermolecularly [10].

Chemical compound and disease context of Gad2

  • The results suggest that GABA generated by either GAD65 or GAD67 is not critically involved in islet formation and that GAD65 expression is not an absolute requirement for development of autoimmune diabetes in the NOD mouse [11].

Biological context of Gad2

  • Furthermore, at the low penetrance of diabetes in this backcross, GAD65-deficient mice developed disease at the same rate and incidence as wildtype mice [11].
  • The smaller form of the autoantigen glutamic acid decarboxylase, GAD65 (formerly the 64,000 M(r) autoantigen), is a major target of humoral autoimmunity in type I diabetes [2].
  • We here show that the dimerization region in GAD65 is distinct from the NH(2)-terminal membrane-anchoring region and that a membrane anchoring GAD65 subunit can indeed target a soluble subunit to membrane compartments by dimerization [12].
  • However, freezing was reduced and flight and escape behavior were increased in GAD65-/- mice compared to their wild type and heterozygous littermates, while corticosterone levels and defecation rates did not differ between genotypes [13].
  • GAD65 peptides displaying the human histocompatibility leukocyte antigen (HLA)-A*0201 binding motif have been synthesized [14].

Anatomical context of Gad2

  • Yet GAD65 has been shown to be a target of very early autoimmune T-cell responses associated with beta-cell destruction in the non-obese diabetic (NOD) mouse model of Type 1 diabetes [11].
  • Lack of either GAD65 or GAD67 did not effect the development of islet cells and the general morphology of islets [11].
  • Furthermore, in GAD65-/- mouse brain, GAD67, which no longer partitions into the Triton X-114 detergent phase, still anchors to membranes at similar levels as in wild-type mice [12].
  • No significant effects were observed with lymphocytes transduced with gad65 and sgad55 constructs at low m.o.i. By contrast, at high m.o.i., lymphocytes transduced with the sgad55 and seap constructs caused a decrease in insulitis and blood glucose levels and in insulitis alone, respectively [15].
  • In contrast, only about half of GAD65 (which is found in synaptic terminals) exists as active holoenzyme [16].

Associations of Gad2 with chemical compounds

  • Therefore, these results do not support the hypothesis of an involvement of Gad1 or Gad2 in the pathophysiology of acute ethanol withdrawal severity and the other ethanol related traits [17].
  • The separate role of the two isoforms is unknown, but differences in saturation with cofactor and subcellular localization suggest that GAD65 may provide reserve pools of GABA for regulation of inhibitory neurotransmission [18].
  • Additionally, GAD65-deficient mice have a diminished response to the anxiolytics diazepam and pentobarbital, both of which interact with GABA-A receptors in a GABA-dependent fashion to facilitate GABAergic neurotransmission [19].
  • This effect was not observed for GAD65 or neuronal-specific enolase and was not replicated by glycine doses 2-fold greater than those of l-methionine [20].
  • This partial cDNA shows 90% identity with mammalian GAD 65 and presents the Asn-Pro-His-Lys (NPHK) sequence corresponding to the pyridoxal-binding region of porcine DOPA decarboxylase or mammalian GAD [21].

Regulatory relationships of Gad2


Other interactions of Gad2

  • GAD 67 mRNA was more abundant than GAD 65, and both were localized to islet beta-cells by in situ hybridization [1].
  • Seizure susceptibility is dramatically increased in GAD65-/- mice backcrossed into a second genetic background, the nonobese diabetic (NOD/LtJ) strain of mice enabling electroencephalogram analysis of the seizures [18].
  • These data suggest that GABA synthesized by GAD65 is important in the dynamic regulation of neural network excitability, implicate at least one modifier locus in the NOD/LtJ strain, and present GAD65-/- animals as a model of epilepsy involving GABA-ergic pathways [18].
  • Using an RNase protection assay, both GAD 65 and GAD 67 mRNAs were detected in the rodent small intestine [24].
  • NCAM-EC transgenic mice exhibited a striking reduction in synaptic puncta of GABAergic interneurons in the cingulate, frontal association cortex, and amygdala but not hippocampus, as shown by decreased immunolabeling of glutamic acid decarboxylase-65 (GAD65), GAD67, and GABA transporter 1 [25].

Analytical, diagnostic and therapeutic context of Gad2


  1. Localization and quantitation of expression of two glutamate decarboxylase genes in pancreatic beta-cells and other peripheral tissues of mouse and rat. Faulkner-Jones, B.E., Cram, D.S., Kun, J., Harrison, L.C. Endocrinology (1993) [Pubmed]
  2. Differential expression of GAD65 and GAD67 in human, rat, and mouse pancreatic islets. Kim, J., Richter, W., Aanstoot, H.J., Shi, Y., Fu, Q., Rajotte, R., Warnock, G., Baekkeskov, S. Diabetes (1993) [Pubmed]
  3. GABA and histogenesis in fetal and neonatal mouse brain lacking both the isoforms of glutamic acid decarboxylase. Ji, F., Kanbara, N., Obata, K. Neurosci. Res. (1999) [Pubmed]
  4. Modulating autoimmune responses to GAD inhibits disease progression and prolongs islet graft survival in diabetes-prone mice. Tian, J., Clare-Salzler, M., Herschenfeld, A., Middleton, B., Newman, D., Mueller, R., Arita, S., Evans, C., Atkinson, M.A., Mullen, Y., Sarvetnick, N., Tobin, A.J., Lehmann, P.V., Kaufman, D.L. Nat. Med. (1996) [Pubmed]
  5. Widespread expression of an autoantigen-GAD65 transgene does not tolerize non-obese diabetic mice and can exacerbate disease. Geng, L., Solimena, M., Flavell, R.A., Sherwin, R.S., Hayday, A.C. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  6. Experience-dependent pruning of dendritic spines in visual cortex by tissue plasminogen activator. Mataga, N., Mizuguchi, Y., Hensch, T.K. Neuron (2004) [Pubmed]
  7. Cleft palate and decreased brain gamma-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase. Asada, H., Kawamura, Y., Maruyama, K., Kume, H., Ding, R.G., Kanbara, N., Kuzume, H., Sanbo, M., Yagi, T., Obata, K. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  8. Inhibitory threshold for critical-period activation in primary visual cortex. Fagiolini, M., Hensch, T.K. Nature (2000) [Pubmed]
  9. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Tisch, R., Yang, X.D., Singer, S.M., Liblau, R.S., Fugger, L., McDevitt, H.O. Nature (1993) [Pubmed]
  10. Nasal administration of glutamate decarboxylase (GAD65) peptides induces Th2 responses and prevents murine insulin-dependent diabetes. Tian, J., Atkinson, M.A., Clare-Salzler, M., Herschenfeld, A., Forsthuber, T., Lehmann, P.V., Kaufman, D.L. J. Exp. Med. (1996) [Pubmed]
  11. Glutamate decarboxylase and GABA in pancreatic islets: lessons from knock-out mice. Kash, S.F., Condie, B.G., Baekkeskov, S. Horm. Metab. Res. (1999) [Pubmed]
  12. The hydrophilic isoform of glutamate decarboxylase, GAD67, is targeted to membranes and nerve terminals independent of dimerization with the hydrophobic membrane-anchored isoform, GAD65. Kanaani, J., Lissin, D., Kash, S.F., Baekkeskov, S. J. Biol. Chem. (1999) [Pubmed]
  13. Altered conditioned fear behavior in glutamate decarboxylase 65 null mutant mice. Stork, O., Yamanaka, H., Stork, S., Kume, N., Obata, K. Genes Brain Behav. (2003) [Pubmed]
  14. Cytotoxic T cells specific for glutamic acid decarboxylase in autoimmune diabetes. Panina-Bordignon, P., Lang, R., van Endert, P.M., Benazzi, E., Felix, A.M., Pastore, R.M., Spinas, G.A., Sinigaglia, F. J. Exp. Med. (1995) [Pubmed]
  15. Decreased insulitis and blood glucose levels after injection of GAD-transduced lymphocytes into NOD mice. Li, F., Filippova, M., Fagoaga, O., Nehlsen-Cannarella, S., Escher, A. Mol. Ther. (2002) [Pubmed]
  16. Two forms of the gamma-aminobutyric acid synthetic enzyme glutamate decarboxylase have distinct intraneuronal distributions and cofactor interactions. Kaufman, D.L., Houser, C.R., Tobin, A.J. J. Neurochem. (1991) [Pubmed]
  17. Evaluation of the glutamate decarboxylase genes Gad1 and Gad2 as candidate genes for acute ethanol withdrawal severity in mice. Fehr, C., Rademacher, B.L., Buck, K.J. Prog. Neuropsychopharmacol. Biol. Psychiatry (2003) [Pubmed]
  18. Epilepsy in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase. Kash, S.F., Johnson, R.S., Tecott, L.H., Noebels, J.L., Mayfield, R.D., Hanahan, D., Baekkeskov, S. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  19. Increased anxiety and altered responses to anxiolytics in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase. Kash, S.F., Tecott, L.H., Hodge, C., Baekkeskov, S. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  20. An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability. Tremolizzo, L., Carboni, G., Ruzicka, W.B., Mitchell, C.P., Sugaya, I., Tueting, P., Sharma, R., Grayson, D.R., Costa, E., Guidotti, A. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  21. Distribution of glutamic acid decarboxylase mRNA in the forebrain of the rainbow trout as studied by in situ hybridization. Anglade, I., Mazurais, D., Douard, V., Le Jossic-Corcos, C., Mañanos, E.L., Michel, D., Kah, O. J. Comp. Neurol. (1999) [Pubmed]
  22. Regulatory cytokine production stimulated by DNA vaccination against an altered form of glutamic acid decarboxylase 65 in nonobese diabetic mice. Glinka, Y., De Pooter, R., Croze, F., Prud'homme, G.J. J. Mol. Med. (2003) [Pubmed]
  23. GABAergic phenotypic differentiation of a subpopulation of subventricular derived migrating progenitors. De Marchis, S., Temoney, S., Erdelyi, F., Bovetti, S., Bovolin, P., Szabo, G., Puche, A.C. Eur. J. Neurosci. (2004) [Pubmed]
  24. Transcription and translation of two glutamate decarboxylase genes in the ileum of rat, mouse and guinea pig. Williamson, S., Faulkner-Jones, B.E., Cram, D.S., Furness, J.B., Harrison, L.C. J. Auton. Nerv. Syst. (1995) [Pubmed]
  25. Neural cell adhesion molecule-secreting transgenic mice display abnormalities in GABAergic interneurons and alterations in behavior. Pillai-Nair, N., Panicker, A.K., Rodriguiz, R.M., Gilmore, K.L., Demyanenko, G.P., Huang, J.Z., Wetsel, W.C., Maness, P.F. J. Neurosci. (2005) [Pubmed]
  26. Synaptic vesicle protein synaptoporin is differently expressed by subpopulations of mouse hippocampal neurons. Singec, I., Knoth, R., Ditter, M., Hagemeyer, C.E., Rosenbrock, H., Frotscher, M., Volk, B. J. Comp. Neurol. (2002) [Pubmed]
  27. Quantitative thresholds of MHC class II I-E expressed on hemopoietically derived antigen-presenting cells in transgenic NOD/Lt mice determine level of diabetes resistance and indicate mechanism of protection. Hanson, M.S., Cetkovic-Cvrlje, M., Ramiya, V.K., Atkinson, M.A., Maclaren, N.K., Singh, B., Elliott, J.F., Serreze, D.V., Leiter, E.H. J. Immunol. (1996) [Pubmed]
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