Abstract：
:Neuroactive steroids are efficacious potentiators of GABA-A receptors. Recent work has identified a site in the alpha1 subunit of the GABA-A receptor, that is essential for potentiation by steroids. However, each receptor contains two copies of the alpha1 subunit. We generated concatemers of subunits so that the alpha1 subunits could be mutated separately and examined the consequences of mutations that remove potentiation by most neurosteroids (alpha1 Q241L, alpha1 Q241W). Concatemers were expressed in Xenopus laevis oocytes, and activation by GABA, potentiation by neurosteroids, and the agonist activity of piperidine-4-sulfonic acid (P4S) were determined. When the alpha1 Q241L mutation is present in alpha1 subunits the EC(50) for activation by GABA is shifted to higher concentration and potentiation by neurosteroids is diminished. When the alpha1 Q241W mutation is expressed, the EC(50) for GABA is shifted to lower concentration, the relative efficacy of P4S is increased, and potentiation by neurosteroids is diminished. Mutation of only one alpha1 subunit does not produce the full effect of mutating both sites. Overall, the data demonstrate that at a macroscopic level, the presence of a single wild-type steroid-binding site is sufficient to mediate responses to steroid, but both must be mutated to completely remove the effects of steroids. Differences between the two sites seem to be relatively subtle.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Bracamontes JR,Steinbach JHdoi
10.1124/mol.108.053629subject
Has Abstractpub_date
2009-04-01 00:00:00pages
973-81issue
4eissn
0026-895Xissn
1521-0111pii
mol.108.053629journal_volume
75pub_type
杂志文章abstract：:Some biochemical and pharmacological properties of a novel, potent inhibitor of cyclic AMP phosphodiesterase, N-cyclohexyl-N-methyl-4-(7-oxy-1,2,3,5-tetrahydroimidazo[2,1-b] quinazolin-2-one) butyramide (RS-82856), were investigated. RS-82856 selectively inhibits the high affinity form of cyclic AMP phosphodiesterase ...
journal_title：Molecular pharmacology
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journal_title：Molecular pharmacology
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journal_title：Molecular pharmacology
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更新日期：1997-04-01 00:00:00
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journal_title：Molecular pharmacology
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journal_title：Molecular pharmacology
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doi：
更新日期：1986-01-01 00:00:00
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doi：
更新日期：1993-08-01 00:00:00
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journal_title：Molecular pharmacology
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doi：
更新日期：1993-06-01 00:00:00
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更新日期：1999-05-01 00:00:00
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更新日期：1986-09-01 00:00:00
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更新日期：1994-07-01 00:00:00
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doi：
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更新日期：1990-08-01 00:00:00
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pub_type： 杂志文章
doi：
更新日期：1995-08-01 00:00:00
