Abstract:
:We examined the block of N-methyl-D-aspartate (NMDA) receptors by n-alkyl (straight chain) diamines and related monoamines and triamines using whole-cell voltage clamp recording of NMDA receptor currents in cultured rat hippocampal neurons and [3H] dizocilpine binding to rat forebrain homogenates. At -60 mV, the diamines (carbon chain lengths 3-12) produced a concentration-dependent inhibition of NMDA receptor current (IC50 values, 6128-7.3 microM). For diamines of carbon chain lengths greater than 6, the inhibition was partially, but not completely, relieved by depolarization, indicating that the block occurs at distinct voltage-dependent and voltage-independent sites. The block produced by short-chain diamines (carbon chain lengths 3-6) was completely relieved by depolarization, indicating little or no interaction with the voltage-independent site. In comparison with the corresponding diamines, homologous monoamines exhibited very low potency, whereas homologous triamines were of equal or lower potency. For long-chain diamines, inhibitory potency at both the voltage-dependent and voltage-independent sites was correlated with carbon chain length (binding energy increasing 600-700 cal/mol-CH2), suggesting that binding to each of the sites is stabilized by a hydrophobic interaction. Affinities for the voltage-dependent blocking site (transformed to 0 mV) and for the voltage-independent blocking site were similar. These values were also similar to the inhibitory potencies of the diamines in the [3H]dizocilpine binding assay. Analysis of the voltage-dependence of block at the voltage-dependent site yielded z delta values for diamines of intermediate length (carbon chain lengths 7-9) that decreased with increasing length from 0.91 to 0.63 [approaching the z delta values of monovalent blockers (approximately 0.54) and one-half of the z delta values of shorter diamines (approximately 1.1)], suggesting that the intermediate length diamines block in a linear, extended chain conformation with one of the charges having incomplete access to a deep binding site. Longer chain diamines (carbon chain lengths 10 and 12) exhibited larger z delta values (0.78 and 0.98, respectively), presumably because enhanced conformational flexibility permitted a folded-over conformation. From the interchange distances of the intermediate length diamines in their lowest energy conformation, we estimated that the total voltage drop within the NMDA receptor channel occurs over a distance of approximately 20 A. The putative polyamine facilitatory site antagonist diethylenetriamine inhibited NMDA-induced currents at the voltage-dependent site (IC50, 654 microM; -60 mV).(ABSTRACT TRUNCATED AT 400 WORDS)
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Subramaniam S,Donevan SD,Rogawski MAsubject
Has Abstractpub_date
1994-01-01 00:00:00pages
117-24issue
1eissn
0026-895Xissn
1521-0111journal_volume
45pub_type
杂志文章abstract::The effect of ethanol on intracellular ionized calcium concentrations (Cai) was studied in synaptosomes isolated from mouse whole brain and in hepatocytes isolated from rat liver. The fluorescent calcium chelator, fura-2, was used to quantitate Cai. Incubation of synaptosomes with ethanol (350-700 mM) increased restin...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1987-12-01 00:00:00
abstract::Stimulation of beta2-adrenoceptors with the selective beta2 agonist procaterol caused a biphasic decrease in cell surface M2 muscarinic receptor number in human embryonic lung 299 cells when measured with the hydrophilic antagonist [3H]N-methylscopolamine. In contrast, total muscarinic receptor number, measured with t...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1996-04-01 00:00:00
abstract::Fusion proteins were generated between the human 5-hydroxytryptamine (5-HT)(1A) receptor and both wild-type (Cys(351)) and pertussis toxin-resistant (Gly(351) and Ile(351)) forms of G(i1). These were expressed stably. Pertussis toxin treatment substantially reduced basal high-affinity GTPase activity in clones express...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1999-10-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-06-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.62.3.722
更新日期:2002-09-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-07-01 00:00:00
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pub_type: 杂志文章
doi:10.1124/mol.109.058628
更新日期:2009-11-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.109.062216
更新日期:2010-08-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.109.055897
更新日期:2009-08-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.64.6.1494
更新日期:2003-12-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-05-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.64.3.640
更新日期:2003-09-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.56.1.185
更新日期:1999-07-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.108.054155
更新日期:2009-05-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-02-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.61.5.1025
更新日期:2002-05-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.015628
更新日期:2005-12-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-10-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
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更新日期:2000-08-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1992-04-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1992-01-01 00:00:00
abstract::Ethanol administration to rats by ethanol vapor inhalation (14 days) results in a 40-50% reduction in the level of gamma-aminobutyric acidA (GABAA) receptor alpha 1 subunit mRNAs [4.4 and 4.8 kilobases (kb)] in the cerebral cortex. The level of alpha 2 subunit mRNA (8.0 kb) was also reduced by 29%, whereas there was n...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1991-02-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/molpharm.120.000061
更新日期:2020-12-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-01-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.59.1.24
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journal_title:Molecular pharmacology
pub_type: 杂志文章
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1982-07-01 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章
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更新日期:1997-12-01 00:00:00
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pub_type: 杂志文章
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更新日期:1999-08-01 00:00:00