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Relationship between I2 Imidazoline Binding Sites and Monoamine Oxidase B in Liver

Authors

  • A. REMAURY,

    1. I.N.S.E.R.M. U.388 Pharmacologie Moléculaire et Physiopathologie rénale, Institut Louis Bugnard, C.H.U. Rangeuil, 31403 Toulouse Cédex 4, France
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  • C. ORDENER,

    1. I.N.S.E.R.M. U.388 Pharmacologie Moléculaire et Physiopathologie rénale, Institut Louis Bugnard, C.H.U. Rangeuil, 31403 Toulouse Cédex 4, France
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  • J. SHIH,

    1. I.N.S.E.R.M. U.388 Pharmacologie Moléculaire et Physiopathologie rénale, Institut Louis Bugnard, C.H.U. Rangeuil, 31403 Toulouse Cédex 4, France
    2. Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, California 90033, USA
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  • A. PARINI

    Corresponding author
    1. I.N.S.E.R.M. U.388 Pharmacologie Moléculaire et Physiopathologie rénale, Institut Louis Bugnard, C.H.U. Rangeuil, 31403 Toulouse Cédex 4, France
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Address for correspondence: Dr. Angelo Parini, I.N.S.E.R.M. U.388-Institut Louis Bugnard-C.H.U. Rangueil-Bât. L3, 31403 Toulouse Cédex 04, France. Phone, (33) 05 61 32 22 10; fax, (33) 05 62 17 25 54; e-mail, parini@rangueil.inserm.fr

Abstract

ABSTRACT: Biochemical and pharmacologic studies suggest that I2 imidazoline binding sites (I2BS) represent a heterogeneous family of membrane proteins. Indeed, the imidazoline binding sites located on monoamine oxidases (MAO) A and B display different pharmacologic properties. Recent results suggest that in liver and brain, I2BS may be located on proteins distinct from MAOs. The following observations indicate that in liver and brain, [3H]idazoxan binds exclusively to I2BS located on MAO-B: (1) size exclusion chromatography of digitonin-solubilized preparations from rabbit and human liver showed that [3H]idazoxan-specific binding eluted only in two peaks (∼175,000 and ∼100,000 Da, corresponding to 90% and 10% of the recovered [3H]idazoxan binding) which also contained MAOs as determined by [14C]tyramine oxidation and Western blot analysis; (2) according to previous results obtained in various human and rat tissues, experiments performed in mice liver and brain showed that idazoxan was a potent inhibitor of [125I]-AZIPI photoincorporation to MAO-B but not to MAO-A; (3) in MAO-deficient transgenic mice, [3H]idazoxan binding to liver and brain membranes was completely abolished in MAO-B knockout mice and was not affected in MAO-A knockout mice. Together, these results show that in both liver and brain, I2BS are located exclusively on MAO-B. The imidazoline binding site on MAO-A, which photoincorporates [125I]-AZIPI and displays a low affinity for idazoxan, may not belong to the family of the I2 imidazoline binding sites.

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