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Identification of inosine as an endogenous modulator for the benzodiazepine binding site of the GABAA receptors

  • Original Paper
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Journal of Biomedical Science

Abstract

Previously we have reported the presence of endogenous ligands that are involved in the regulation of the binding of muscimol to the GABA binding site of the GABAA receptors. Here, we report the presence of multiple forms of endogenous ligands in the brain which modulate the binding of flunitrazepam (FNZP) to the benzodiazepine (BZ) binding site of the GABAA receptor. Furthermore, one of the endogenous ligands for the BZ receptors, referred to as EBZ, has been identified as inosine based on the following observations: (1) standard inosine and the EBZ have identical NMR and UV spectra; (2) the elution profile of inosine and the EBZ from a HPLC column are indistinguishable, and (3) inosine and the EBZ show identical activity in inhibiting [3H]FNZP binding.

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References

  1. Asano T, Spector S. Identification of inosine and hypoxanthine as endogenous ligands for the brain benzodiazepine-binding sites. Proc Natl Acad Sci USA, 76:977–981:1979.

    PubMed  Google Scholar 

  2. Barnard EA. The molecular biology of GABAA receptors and its applications. In: Tanaka C, Bowery NG, eds. GABA: Receptors, Transporters and Metabolism. Basel, Birkhäuser, 129–144;1996.

    Google Scholar 

  3. Bowery NG. Baclofen: 10 years on. Trends Pharmacol Sci 3:400–403;1983.

    Article  Google Scholar 

  4. Braestrup C, Nielsen M, Olsen CE. Urinary and brain β-carboline-3-carboxylates as potent inhibitors of brain benzodiazepine receptors. Proc Natl Acad Sci USA 77:2288–2292;1980.

    PubMed  Google Scholar 

  5. Enna SJ, Gallagher JP. Biochemical and electrophysiological characteristics of mammalian GABA receptors. Int Rev Neurobiol 24:181–212;1983.

    PubMed  Google Scholar 

  6. Guidotti A, Forchetti MC, Corda MG, Konkel D, Bennett CD, Costa E. Isolation, characterization, and purification to homogeneity of an endogenous polypeptide with agonistic action on benzodiazepine receptors. Proc Natl Acad Sci USA 80:3531–3533;1983.

    PubMed  Google Scholar 

  7. Haefely WE. Pharmacology of the benzodiazepine receptor. Eur Arch Psychiatry Neurol Sci 238:294–301;1989.

    Article  PubMed  Google Scholar 

  8. Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Morgan BA, Morris HR. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 258:577–579;1975.

    Google Scholar 

  9. Javier V, Park D, Chin G, de Blas AL. Monoclonal antibodies and conventional antisera to the GABAA receptor/benzodiazepine receptor/Cl-channel complex. J Neurosci 8:615–622;1988.

    PubMed  Google Scholar 

  10. Johnston GAR. GABAC receptors. Prog Brain Res 100:61–65;1995.

    Google Scholar 

  11. Johnston GAR, Allan RD. GABA agonists. Neuropharmacology, 23:831–832;1984.

    Article  Google Scholar 

  12. Johnston GAR, Kennedy SME. GABA receptors and phospholipids. In: Fonnum F, ed. Amino Acids as Chemical Transmitters. New York, Plenum, 507–516;1978.

    Google Scholar 

  13. Johnston GAR, Kennedy SME. Endogenous inhibitors of GABA binding to rat brain membranes. Clin Exp Pharmacol Physiol 6:686–687;1979.

    Google Scholar 

  14. Kaupmann K, Huggel K, Heid J, Flor PJ, Bischoff S, Mickel SJ, McMaster G, Angst C, Bittiger H, Froestl W, Bettler B. Expression cloning of GABAB receptors uncovers similarity to metabotropic glutamate receptors. Nature 386:239–246;1997.

    Article  PubMed  Google Scholar 

  15. Khandelwal JK, Prell GD, Morrishow AM, Green JP. Presence and measurement of imidazole acetic acid, γ-aminobutyric acid agonist, in rat brain and human cerebrospinal fluid. J Neurochem 52:1107–1113;1989.

    PubMed  Google Scholar 

  16. Levitan ES, Schofield PR, Burt DR, Rhee LM, Wisden W, Kohler M, Fujita N, Rodriguez HF, Stephenson A, Darlison MG, Barnard EA, Seeburg PH. Structural and functional basis for GABA receptor heterogeneity. Nature 33:76–79;1988.

    Article  Google Scholar 

  17. Liao CC, Lin HS, Liu JY, Hibbard LS, Wu JY. Purification and characterization of a benzodiazepine-like substance from mammalian brain. Neurochem Res 14:345–352;1989.

    Article  PubMed  Google Scholar 

  18. Lüddens H, Korpi ER, Seeburg PH. GABAA/benzodiazepine receptor heterogeneity: Neurophysiological implications. Neuropharmacology 34:245–254;1995.

    Article  PubMed  Google Scholar 

  19. Marangos PJ, Paul SM, Grenlaw P, Goodwin FK, Skolnick P. Demonstration of an endogenous, competitive inhibitor(s) of [3H]diazepam binding in bovine brain. Life Sci 22:1893–1900;1978.

    Article  PubMed  Google Scholar 

  20. Montpied P, Martin BM, Cottingham SL, Stubblefield BK, Ginns EI, Paul SM. Regional distribution of the GABAA/benzodiazepine receptor (α-subunit) mRNA in rat brain. J Neurochem 51:1651–1654;1988.

    PubMed  Google Scholar 

  21. Nicoll R. The coupling of neurotransmitter receptors to ion channels in the brain. Science 241:545–551;1988.

    PubMed  Google Scholar 

  22. Olsen RW, Sapp DM, Bureau MH, Turner DM, Kokka N. Allosteric actions of central nervous system depressants including anesthetics on subtypes of the inhibitory γ-aminobutyric acidA receptor-chloride channel complex. Ann NY Acad Sci 625:145–154;1991.

    PubMed  Google Scholar 

  23. Olsen RW, Tobin AJ. Molecular biology of GABAA receptors. FASEB J 4:1469–1480;1990.

    PubMed  Google Scholar 

  24. Olsen RW, van-Ness P, Napias C, Bergman M, Tourtellotte WW. GABA receptor binding and endogenous inhibitors in normal human brain and Huntington's disease. In: Pepu G, Kuhar MJ, Enna SJ, eds. Receptors for Neurotransmitters and Peptide Hormones. New York, Raven, 451–460;1980.

    Google Scholar 

  25. Pena C, Medina JH, Novas ML, Paladini AC, DeRobertis E. Isolation and identification in bovine cerebral cortex of n-butyl β-carboline-3-carboxylate, a potent benzodiazepine binding inhibitor. Proc Natl Acad Sci USA 83:4952–4596;1986.

    PubMed  Google Scholar 

  26. Pert CB, Pasternak G, Snyder SH. Opiate agonists and antagonists discriminated by receptor binding in brain. Science 182:1359–1361;1973.

    PubMed  Google Scholar 

  27. Roberts E. GABA in nervous system function — An overview. In: Tower BD, ed. The Nervous System, vol 1: The Basic Neurosciences, New York, Raven, 541–552;1975.

    Google Scholar 

  28. Sangameswaran L, Fales HM, Friedrich P, DeBlas AL: Purification of a benzodiazepine from bovine brain and detection of benzodiazepine-like immunoreactivity in human brain. Proc Natl Acad Sci USA 83:9236–9240;1986.

    PubMed  Google Scholar 

  29. Simonyi M. Search for an endogenous GABA antagonist. In: Vartanian ME, ed. Neuronal Receptors, Endogenous Ligands and Biotechnical Approaches. New York, International Universities Press, 69–104;1988.

    Google Scholar 

  30. Skolnick P, Marangos PJ, Goodwin FK, Edwards M, Paul S. Identification of inosine and hypoxanthine as endogenous inhibitors of [3H]diazepam binding in the central nervous system. Life Sci 23:1473–1480;1978.

    Article  PubMed  Google Scholar 

  31. Tanaka C, Bowery NG. GABA: Receptors, Transporters and Metabolism. Basel, Birkhäuser, 1996.

    Google Scholar 

  32. Tang XW, Yarom M, Carlson RG, Vander-Velde D, Huang PY, Lee Y, Seah EC, Deupree D, Wu JY. Isolation of endogenous modulators for the GABA binding site of the GABAA receptor. Neurochem Int 23:485–493;1993.

    Article  PubMed  Google Scholar 

  33. Teoh M, Malcangio M, Bowery NG. GABAB receptor control of transmitter release in the spinal cord. In: Tanaka C, Bowery NG, eds. GABA: Receptor, Transporters and Metabolism. Basel, Birkhäuser, 95–102;1996.

    Google Scholar 

  34. Wojcik WT, Neff NH. Adenosine A1 and GA-BAB receptors may share common postrecognition site elements of the adenylate cyclase complex. Sci Neurosci Abstr 9:1127;1983.

    Google Scholar 

  35. Wu JY, Liao CC, Lee YH, Ho JY, Lin CJ, Lin CY, Tsai WH, Chang KJ. Brain glutamate and GABA receptor-purification and endogenous modulation. Abstract of the International Symposium on Neurotransmission and Signal Transduction, 1989, p 13.

  36. Wu JY, Tang XW, Tsai WH. Taurine receptor: Kinetic analysis and pharmacological studies. In: Lombardini JB, Schaffer SW, Azuma J, eds. Taurine: Nutritional Value and Mechanisms and Action. New York, Plenum, 263–268;1992.

    Google Scholar 

  37. Yarom M, Bao J, Tang XW, Wu E, Lee Y, Tsai WH, Wu JY. Isolation and characterization of endogenous modulators for GABA system. Neurochem Res 17:107–114;1992.

    Article  PubMed  Google Scholar 

  38. Yoneda Y, Kuriyama K. Presence of low molecular weight endogenous inhibitor of [3H]muscimol binding in synaptic membranes. Nature 285:670–673;1980.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Biochemistry, Cell and Molecular Biology, University of Kansas, 1043 Haworth Hall, 66045-2106, Lawrence, KS, USA

    Mina Yarom, Xiao Wen Tang, Elliott Wu &  Jang-Yen Wu

  2. Department of Chemistry, University of Kansas, Lawrence, Kans., USA

    Robert G. Carlson & David Vander Velde

  3. Department of Physiology, Taipei Medical College, Taipei, Taiwan, ROC

    Xi-Hsuan Lee

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  1. Mina Yarom
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  2. Xiao Wen Tang
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Yarom, M., Tang, X.W., Wu, E. et al. Identification of inosine as an endogenous modulator for the benzodiazepine binding site of the GABAA receptors. J Biomed Sci 5, 274–280 (1998). https://doi.org/10.1007/BF02255859

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  • DOI: https://doi.org/10.1007/BF02255859

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