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Titolo:
Mutation of structural determinants lining the N-methyl-D-aspartate receptor channel differentially affects phencyclidine block and spermine potentiation and block
Autore:
Zheng, X; Zhang, L; Wang, AP; Araneda, RC; Lin, Y; Zukin, RS; Bennett, MVL;
Indirizzi:
Yeshiva Univ Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA Yeshiva Univ Albert Einstein Coll Med Bronx NY USA 10461 nx, NY 10461 USA
Titolo Testata:
NEUROSCIENCE
fascicolo: 1, volume: 93, anno: 1999,
pagine: 125 - 134
SICI:
0306-4522(1999)93:1<125:MOSDLT>2.0.ZU;2-7
Fonte:
ISI
Lingua:
ENG
Soggetto:
SUBUNIT-SPECIFIC POTENTIATION; RECOMBINANT NMDA RECEPTORS; PROTEIN-KINASE-C; GLUTAMATE-RECEPTOR; AMINO-ACID; SINGLE-CHANNEL; CYTOPLASMIC POLYAMINES; INWARD RECTIFICATION; HIPPOCAMPAL-NEURONS; EXTRACELLULAR MG2+;
Keywords:
polyamines; phencyclidine; NMDA channel; site-directed mutagenesis; open channel block;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
50
Recensione:
Indirizzi per estratti:
Indirizzo: Bennett, MVL Yeshiva Univ Albert Einstein Coll Med, Dept Neurosci, 1300 Morris Pk Ave, Bronx, NY 10461 USA Yeshiva Univ Albert Einstein Coll Med 1300Morris Pk Ave Bronx NY USA 10461
Citazione:
X. Zheng et al., "Mutation of structural determinants lining the N-methyl-D-aspartate receptor channel differentially affects phencyclidine block and spermine potentiation and block", NEUROSCIENC, 93(1), 1999, pp. 125-134

Abstract

Spermine and other endogenous polyamines potentiate, block and permeate the N-methyl-D-aspartate receptor channel. To identify structural determinants of the N-methyl-D-aspartate channel that mediate spermine's actions, we generated mutant receptors with asparagine (N) to glutamine (Q) or arginine (R) substitutions in the selectivity filter of the channel. We demonstrate that mutation of the three critical asparagines in this domain differentially affects block by phencyclidine and both potentiation and block by spermine. N-to-Q and N-to-R mutations in the N site of the NR1 subunit (N598 in NR1(011), N619 in NR1(100)) and N-to-Q mutations in the N and N + 1 sites (N595 and N596 in NR2A, respectively) of the NR2 subunit (Q/NN, R/NN, N/QN, N/NQ, Q/QN and Q/NQ receptors) reduced affinity for phencyclidine. The Q/NN receptor showed markedly reduced potentiation by spermine, with little or no change in spermine block. The R/NN receptor showed markedly reduced spermine potentiation and affinity for spermine at its block site. The N/QN, N/NQ and Q/QN mutant receptors showed somewhat enhanced spermine block, while the Q/NQ double mutant exhibited significantly more enhanced spermine block. Thus, the asparagine residues critical to Ca2+ permeability and Mg2+ block of N-methyl-D-aspartate channels are also critical to block by spermine and phencyclidine. To examine the interaction of spermine and phencyclidine within the channel, we performed competition studies. Spermine appeared to compete with phencyclidine for binding to the receptor; however, blocks by phencyclidine andby spermine were not additive. The findings suggest that spermine can bindto a site in the external vestibule of the channel to impede phencyclidinebinding, but allow Na+ influx. (C) 1999 IBRO. Published by Elsevier Science Ltd.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 08/08/20 alle ore 08:14:19