Linked Life Data

8913369

Source:http://linkedlifedata.com/resource/pubmed/id/8913369

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
1996-12-26
pubmed:abstractText
The human gamma-aminobutyric acidA (GABAA) receptor alpha 4 subunit was recently cloned and characterized pharmacologically using radioligand binding techniques. These studies suggested that alpha 4 subunits confer a novel diazepam-insensitive binding site. To further investigate the pharmacology of the alpha 4 subunit, we expressed human alpha 4 beta 2 gamma 2L subunit combinations in oocytes and compared the expression and pharmacology of these receptors with alpha 1 beta 2 gamma 2L, beta 2 gamma 2L, and other possible binary subunit combinations. Apparent GABA affinity was 2-3-fold higher for alpha 4 beta 2 gamma 2L than for alpha 1 beta 2 gamma 2L receptors. Functional modulation of receptors by benzodiazepine-site ligands and other classes of allosteric modulator were assayed over a broad concentration range (0.01-100 microM) on currents that were 10% of the maximum GABA response. Diazepam (0.01-1 microM) did not modulate GABA responses at alpha 4 beta 2 gamma 2L receptors, whereas it increased alpha 1 beta 2 gamma 2L responses by approximately 110%. Bretazenil (0.01-1 microM), a benzodiazepine partial agonist, induced higher efficacy modulation of alpha 4 beta 2 gamma 2L receptors (approximately 83%) than of alpha 1 beta 2 gamma 2L (approximately 25%). The benzodiazepine antagonist flumazenil (0.1-10 microM) unexpectedly potentiated alpha 4 beta 2 gamma 2L responses up to approximately 41%, and the benzodiazepine partial inverse agonist Ro15-4513 (1 microM) potentiated alpha 4 beta 2 gamma 2L responses by approximately 63%. Two other benzodiazepine-site ligands, CGS-9895 and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate, had qualitatively similar effects at alpha 1 beta 2 gamma 2L and alpha 4 beta 2 gamma 2L. Modulators such as pentobarbital, 3 alpha-hydroxy-5 alpha-pregnan-20-one, mefenamic acid, and loreclezole also induced similar potentiation at both subtypes of receptor. The pharmacology conferred by the alpha 4 subunit was similar to that conferred by the alpha 6 subunit, to which it shows highest levels of homology, but the two subunits differ in sensitivity to the beta-carboline methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate. Properties of the alpha 4-containing receptors are consistent with diazepam-insensitive binding sites found in cerebral cortex and other forebrain structures. Characterization of these receptors should further our understanding of mechanisms underlying the behavioral effects of GABA modulators and help in the design of drugs with improved, or novel, therapeutic profiles.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0026-895X
pubmed:author
pubmed:issnType
Print
pubmed:volume
50
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1364-75
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed:year
1996
pubmed:articleTitle
Pharmacology of the human gamma-aminobutyric acidA receptor alpha 4 subunit expressed in Xenopus laevis oocytes.
pubmed:affiliation
CoCensys, Inc., Irvine, California 92618, USA.
pubmed:publicationType
Journal Article