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  A single histidine in GABAA receptors is essential for benzodiazepine agonist binding

Wieland, H. A., Lüddens, H., & Seeburg, P. H. (1992). A single histidine in GABAA receptors is essential for benzodiazepine agonist binding. The Journal of Biological Chemistry, 267(3), 1426-1429. Retrieved from http://www.jbc.org/content/267/3/1426.abstract.

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JBiolChem_267_1992_1426.pdf (Any fulltext), 443KB
 
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Wieland, H. A., Author
Lüddens, Hartmut, Author
Seeburg, Peter H.1, Author           
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1Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497704              

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 Abstract: Benzodiazepines (BZ) modulate neurotransmitter-evoked chloride currents at the gamma-aminobutyric acid type A (GABAA) receptor, the major inhibitory ion channel in the mammalian brain. This receptor is composed of structurally distinct subunits whose numerous molecular variants underlie the observed diversity in the properties of the BZ site. Pharmacologically distinct BZ sites can be recreated by the recombinant coexpression of any one of six alpha subunits, a beta subunit variant, and the gamma 2 subunit. In these receptors the alpha variant determines the affinity for ligand binding of the BZ site. Notably, the alpha 1 and alpha 6 variants impart on alpha chi beta 2 gamma 2 receptors high and negligible affinity, respectively, to BZ ligands with sedative as well as anxiolytic activities. By exchanging domains between the alpha 1 and alpha 6 variants, we show that a portion of the large extracellular domain determines sensitivity toward these ligands. Furthermore, we identify a single histidine residue in the alpha 1 variant, replaced by an arginine in alpha 6, as a major determinant for high affinity binding of BZ agonists. This residue also plays a role in determining high affinity binding for BZ antagonists. Hence, this histidine present in the alpha 1, alpha 2, alpha 3, and alpha 5 subunits appears to be a key residue for the action of clinically used BZ ligands.

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Language(s): eng - English
 Dates: 1991-07-081992-01-25
 Publication Status: Issued
 Pages: 4
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 Table of Contents: -
 Rev. Type: Peer
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Title: The Journal of Biological Chemistry
  Other : JBC
Source Genre: Journal
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Publ. Info: Baltimore, etc. : American Society for Biochemistry and Molecular Biology [etc.]
Pages: - Volume / Issue: 267 (3) Sequence Number: - Start / End Page: 1426 - 1429 Identifier: ISSN: 0021-9258
CoNE: https://pure.mpg.de/cone/journals/resource/954925410826_1