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Gad2  -  glutamate decarboxylase 2

Rattus norvegicus

Synonyms: 65 kDa glutamic acid decarboxylase, GAD-65, Gad65, Glutamate decarboxylase 2, Glutamate decarboxylase 65 kDa isoform
 
 
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Disease relevance of Gad2

 

High impact information on Gad2

  • These forms, GAD65 and GAD67, derive from two genes [6].
  • Deletion of the first 23 amino acids at the NH2 terminus of the GAD65 30/45A mutant also does not affect the hydrophobicity and membrane anchoring of the GAD65 protein [7].
  • The results suggest that amino acids 24-31 are required for hydrophobic modification and/or targeting of GAD65 to membrane compartments, whereas palmitoylation of Cys 30 and Cys 45 may rather serve to orient or fold the protein at synaptic vesicle membranes [7].
  • Amino acid residues 24-31 but not palmitoylation of cysteines 30 and 45 are required for membrane anchoring of glutamic acid decarboxylase, GAD65 [7].
  • Mutation of Cys 30 and Cys 45 to Ala results in a loss of palmitoylation but does not significantly alter membrane association of GAD65 in COS-7 cells [7].
 

Biological context of Gad2

 

Anatomical context of Gad2

  • The predominant form of GAD in pancreatic beta-cells, GAD65, is synthesized as a soluble hydrophilic molecule, which is modified to become firmly membrane anchored [13].
  • However, c-fos induction was not affected in other forebrain GABAergic stress pathways, such as the lateral septum, medial preoptic area or dorsomedial hypothalamus. vSUB lesions increased GAD65 or GAD67 mRNA levels in several efferent targets, including anterior and posterior subnuclei of the bed nucleus of the stria terminalis and lateral septum [14].
  • Lesions did not effect stress-induced increases in GAD65 expression in principal output nuclei of the amygdala [14].
  • A signal located within amino acids 1-27 of GAD65 is required for its targeting to the Golgi complex region [1].
  • In this study, the cloned genes for GAD-65 and GAD-67 were expressed separately in Chinese hamster ovary (CHO) cells and COS cells [2].
 

Associations of Gad2 with chemical compounds

  • GAD65 and GAD67 are two isoforms of the enzyme glutamic acid decarboxylase which catalyze the production of GABA from glutamate, primarily in the brain [15].
  • The NH2-terminal domain of GAD65 is the site of a two-step modification, the last of which results in a firm membrane anchoring that involves posttranslational hydroxylamine sensitive palmitoylation [13].
  • GABA-C receptor subunits (rho1, rho2, rho3) and GABA synthesizing enzymes (GAD 65 and GAD 67) were shown to be expressed as assayed by RT-PCR, and GABA-C receptor stimulation by CACA obviously increased intracellular Ca2+ concentration in the anterior pituitary cells [16].
  • Two isoforms of glutamic acid decarboxylase (GAD67 and GAD65) and their mRNAs were localized in the rat brain by immunohistochemistry and nonradioactive in situ hybridization methods with digoxigenin-labeled cRNA probes [17].
  • CONCLUSION/INTERPRETATION: These results show that the most active beta cells, which secrete more insulin, also express GAD65 and that manipulating extracellular glucose may modify the expression of the enzyme and possibly the autoimmune attack in Type I diabetes [11].
 

Physical interactions of Gad2

 

Regulatory relationships of Gad2

  • The results suggest that palmitoylation of GAD65 regulates the trafficking of the protein from Golgi membranes to an endosomal trafficking pathway in axons that is dependent on Rab5a and is required for the targeting of several synaptic vesicle proteins to presynaptic clusters [18].
  • In summary: 1) IL-1 beta dramatically inhibits GAD-65 expression [19].
  • Clones expressing GAD65 had higher enzymatic activity than those expressing GAD67 [20].
 

Other interactions of Gad2

  • Palmitoylation controls trafficking of GAD65 from Golgi membranes to axon-specific endosomes and a Rab5a-dependent pathway to presynaptic clusters [18].
  • In contrast, BDNF-up-regulated GABA release and GAD65/67 expression depended on MAPK [21].
  • Expression of both GAD65 and GAD67 mRNA, measured by RNase protection assay, was also decreased by IL-1 beta and completely restored to baseline levels by NMMA [22].
  • Neither the expression of preoptic GnRH mRNA nor the expression of GAD65 and of GnRH-R mRNA in both hypothalamic structures was affected by feed restriction [23].
  • 3) IFN gamma at doses of 10, 100, 1000 U/ml had no effect on insulin secretion or on GAD-65 expression [19].
 

Analytical, diagnostic and therapeutic context of Gad2

References

  1. A signal located within amino acids 1-27 of GAD65 is required for its targeting to the Golgi complex region. Solimena, M., Dirkx, R., Radzynski, M., Mundigl, O., De Camilli, P. J. Cell Biol. (1994) [Pubmed]
  2. Association of GAD-65, but not of GAD-67, with the Golgi complex of transfected Chinese hamster ovary cells mediated by the N-terminal region. Solimena, M., Aggujaro, D., Muntzel, C., Dirkx, R., Butler, M., De Camilli, P., Hayday, A. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  3. Adeno-associated viral glutamate decarboxylase expression in the lateral nucleus of the rat hypothalamus reduces feeding behavior. Noordmans, A.J., Song, D.K., Noordmans, C.J., Garrity-Moses, M., During, M.J., Fitzsimons, H.L., Imperiale, M.J., Boulis, N.M. Gene Ther. (2004) [Pubmed]
  4. GABA synthesis in astrocytes after infection with defective herpes simplex virus vectors expressing glutamic acid decarboxylase 65 or 67. New, K.C., Rabkin, S.D. J. Neurochem. (1998) [Pubmed]
  5. Hypoxia regulates glutamate metabolism and membrane transport in rat PC12 cells. Kobayashi, S., Millhorn, D.E. J. Neurochem. (2001) [Pubmed]
  6. Two genes encode distinct glutamate decarboxylases. Erlander, M.G., Tillakaratne, N.J., Feldblum, S., Patel, N., Tobin, A.J. Neuron (1991) [Pubmed]
  7. Amino acid residues 24-31 but not palmitoylation of cysteines 30 and 45 are required for membrane anchoring of glutamic acid decarboxylase, GAD65. Shi, Y., Veit, B., Baekkeskov, S. J. Cell Biol. (1994) [Pubmed]
  8. Two human glutamate decarboxylases, 65-kDa GAD and 67-kDa GAD, are each encoded by a single gene. Bu, D.F., Erlander, M.G., Hitz, B.C., Tillakaratne, N.J., Kaufman, D.L., Wagner-McPherson, C.B., Evans, G.A., Tobin, A.J. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  9. Phosphorylation of serine residues 3, 6, 10, and 13 distinguishes membrane anchored from soluble glutamic acid decarboxylase 65 and is restricted to glutamic acid decarboxylase 65alpha. Namchuk, M., Lindsay, L., Turck, C.W., Kanaani, J., Baekkeskov, S. J. Biol. Chem. (1997) [Pubmed]
  10. Region-specific regulation of glutamic acid decarboxylase (GAD) mRNA expression in central stress circuits. Bowers, G., Cullinan, W.E., Herman, J.P. J. Neurosci. (1998) [Pubmed]
  11. Heterogeneity in glutamic acid decarboxylase expression among single rat pancreatic beta cells. Sánchez-Soto, M.C., Larrieta, M.E., Vidaltamayo, R., Hiriart, M. Diabetologia (1999) [Pubmed]
  12. Islet autoantibody markers in IDDM: risk assessment strategies yielding high sensitivity. Bonifacio, E., Genovese, S., Braghi, S., Bazzigaluppi, E., Lampasona, V., Bingley, P.J., Rogge, L., Pastore, M.R., Bognetti, E., Bottazzo, G.F. Diabetologia (1995) [Pubmed]
  13. Membrane anchoring of the autoantigen GAD65 to microvesicles in pancreatic beta-cells by palmitoylation in the NH2-terminal domain. Christgau, S., Aanstoot, H.J., Schierbeck, H., Begley, K., Tullin, S., Hejnaes, K., Baekkeskov, S. J. Cell Biol. (1992) [Pubmed]
  14. Regulation of forebrain GABAergic stress circuits following lesion of the ventral subiculum. Mueller, N.K., Dolgas, C.M., Herman, J.P. Brain Res. (2006) [Pubmed]
  15. Characterization of the rat GAD67 gene promoter reveals elements important for basal transcription and glucose responsiveness. Pedersen, A.A., Videbaek, N., Skak, K., Petersen, H.V., Michelsen, B.K. DNA Seq. (2001) [Pubmed]
  16. Gamma-aminobutyric acid (GABA)-C receptor stimulation increases prolactin (PRL) secretion in cultured rat anterior pituitary cells. Nakayama, Y., Hattori, N., Otani, H., Inagaki, C. Biochem. Pharmacol. (2006) [Pubmed]
  17. Comparative localization of two forms of glutamic acid decarboxylase and their mRNAs in rat brain supports the concept of functional differences between the forms. Esclapez, M., Tillakaratne, N.J., Kaufman, D.L., Tobin, A.J., Houser, C.R. J. Neurosci. (1994) [Pubmed]
  18. Palmitoylation controls trafficking of GAD65 from Golgi membranes to axon-specific endosomes and a Rab5a-dependent pathway to presynaptic clusters. Kanaani, J., Diacovo, M.J., El-Husseini, A.e.l.-.D., Bredt, D.S., Baekkeskov, S. J. Cell. Sci. (2004) [Pubmed]
  19. The effect of cytokines on expression of glutamic acid decarboxylase-65 in cultured islets. Hao, W., Palmer, J.P. Autoimmunity (1995) [Pubmed]
  20. Rat-1 fibroblasts engineered with GAD65 and GAD67 cDNAs in retroviral vectors produce and release GABA. Ruppert, C., Sandrasagra, A., Anton, B., Evans, C., Schweitzer, E.S., Tobin, A.J. J. Neurochem. (1993) [Pubmed]
  21. Brain-derived neurotrophic factor-induced potentiation of glutamate and GABA release: different dependency on signaling pathways and neuronal activity. Matsumoto, T., Numakawa, T., Yokomaku, D., Adachi, N., Yamagishi, S., Numakawa, Y., Kunugi, H., Taguchi, T. Mol. Cell. Neurosci. (2006) [Pubmed]
  22. Cytokine regulation of glutamate decarboxylase biosynthesis in isolated rat islets of Langerhans. Schmidli, R.S., Faulkner-Jones, B.E., Harrison, L.C., James, R.F., DeAizpurua, H.J. Biochem. J. (1996) [Pubmed]
  23. Reduction of luteinzing hormone secretion induced by long-term feed restriction in male rats is associated with increased expression of GABA-synthesizing enzymes without alterations of GnRH gene expression. Leonhardt, S., Shahab, M., Luft, H., Wuttke, W., Jarry, H. J. Neuroendocrinol. (1999) [Pubmed]
  24. Autoantibodies in IDDM primarily recognize the 65,000-M(r) rather than the 67,000-M(r) isoform of glutamic acid decarboxylase. Hagopian, W.A., Michelsen, B., Karlsen, A.E., Larsen, F., Moody, A., Grubin, C.E., Rowe, R., Petersen, J., McEvoy, R., Lernmark, A. Diabetes (1993) [Pubmed]
  25. Effects of increased gamma-aminobutyric acid levels on GAD67 protein and mRNA levels in rat cerebral cortex. Rimvall, K., Sheikh, S.N., Martin, D.L. J. Neurochem. (1993) [Pubmed]
  26. Phenobarbital at low dose exerts hormesis in rat hepatocarcinogenesis by reducing oxidative DNA damage, altering cell proliferation, apoptosis and gene expression. Kinoshita, A., Wanibuchi, H., Morimura, K., Wei, M., Shen, J., Imaoka, S., Funae, Y., Fukushima, S. Carcinogenesis (2003) [Pubmed]
 
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