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  Selective antagonist for the cerebellar granule cell-specific gamma-aminobutyric acid type A receptor.

Korpi, E. R., Kuner, T., Seeburg, P. H., & Lüddens, H. (1995). Selective antagonist for the cerebellar granule cell-specific gamma-aminobutyric acid type A receptor. Molecular Pharmacology, 47(2), 283-289. Retrieved from http://molpharm.aspetjournals.org/content/47/2/283.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0019-A809-9 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-AE7D-5
Genre: Journal Article

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MolPharmacol_47_1995_283.pdf (Any fulltext), 2MB
 
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 Creators:
Korpi, Esa R., Author
Kuner, Thomas1, 2, 3, 4, 5, Author              
Seeburg, Peter H.4, Author              
Lüddens, Hartmut, Author
Affiliations:
1Interdisciplinary WIN-Research Group on Olfactory Dynamics, Max Planck Institute for Medical Research, Max Planck Society, ou_1497717              
2Synaptic Transmission MNTB, Max Planck Institute for Medical Research, Max Planck Society, ou_1497745              
3Synaptic Transmission, Max Planck Institute for Medical Research, Max Planck Society, ou_1497744              
4Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497704              
5Department of Cell Physiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497701              

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 Abstract: Numerous ligands affect inhibitory gamma-aminobutyric acid (GABA)A receptors, none of them showing strict receptor subtype specificity. We report here that a cerebellar GABAA receptor subtype can be uniquely modulated by furosemide but not by bumetanide, another Cl-/cation transport blocker. Furosemide specifically reversed the inhibition by GABA of t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding in the cerebellar granule cell layer, as detected by autoradiography of rat brain sections. With recombinant receptors expressed in Xenopus oocytes, furosemide antagonized potently (IC50, about 10 microM), rapidly, and reversibly GABA-evoked currents of cerebellar granule cell-specific alpha 6 beta 2 gamma 2 receptors but not alpha 1 beta 2 gamma 2 receptors (IC50, > 3 mM). Furosemide reversed GABA inhibition of [35S]TBPS binding and elevated basal [35S]TBPS binding only with alpha 6 beta 2 gamma 2 and alpha 6 beta 3 gamma 2 receptors and not with alpha 6 beta 1 gamma 2 or alpha 1 beta 1/2/3 gamma 2 receptors. It appeared to interact with the receptor complex via a novel recognition site that allosterically regulates the Cl- ionophore. Furosemide is the first subtype-selective GABAA receptor (alpha 6 beta 2/3 gamma 2) antagonist and should facilitate studies on cerebellar physiology. It might serve as a prototypic structure for the development of additional subtype-selective GABAA ligands.

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Language(s): eng - English
 Dates: 1994-10-041994-11-181995-02-01
 Publication Status: Published in print
 Pages: 7
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 Rev. Type: Peer
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Title: Molecular Pharmacology
  Other : Mol. Pharmacol.
Source Genre: Journal
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Publ. Info: Bethesda, Md. : American Society for Pharmacology and Experimental Therapeutics
Pages: - Volume / Issue: 47 (2) Sequence Number: - Start / End Page: 283 - 289 Identifier: ISSN: 0026-895X
CoNE: https://pure.mpg.de/cone/journals/resource/954925426203