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Titolo:
HOMOLOGOUS MUTATIONS ON DIFFERENT SUBUNITS CAUSE UNEQUAL BUT ADDITIVEEFFECTS ON N-ALCOHOL BLOCK IN THE NICOTINIC RECEPTOR PORE
Autore:
FORMAN SA;
Indirizzi:
MASSACHUSETTS GEN HOSP,DEPT ANESTHESIA,CLN-3 BOSTON MA 02114
Titolo Testata:
Biophysical journal
fascicolo: 5, volume: 72, anno: 1997,
pagine: 2170 - 2179
SICI:
0006-3495(1997)72:5<2170:HMODSC>2.0.ZU;2-2
Fonte:
ISI
Lingua:
ENG
Soggetto:
AFFINITY BINDING-SITE; ACETYLCHOLINE-RECEPTOR; ION CHANNEL; H-3 CHLORPROMAZINE; ALPHA-SUBUNIT; DELTA-SUBUNIT; AMINO-ACIDS; NONCOMPETITIVE ANTAGONIST; GAMMA-SUBUNIT; M2 DOMAIN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
43
Recensione:
Indirizzi per estratti:
Citazione:
S.A. Forman, "HOMOLOGOUS MUTATIONS ON DIFFERENT SUBUNITS CAUSE UNEQUAL BUT ADDITIVEEFFECTS ON N-ALCOHOL BLOCK IN THE NICOTINIC RECEPTOR PORE", Biophysical journal, 72(5), 1997, pp. 2170-2179

Abstract

Hydrophobic antagonists of the nicotinic acetylcholine receptor inhibit channel activity by binding within the transmembrane pore formed bythe second of four transmembrane domains (M2) on each of the receptor's subunits. Hydrophobic mutagenesis near the middle (10 ' locus) of the alpha-subunit M2 domain results in channels that are much more sensitive to block by long-chain alcohols and general anesthetics, indicating that the inhibitory site on wild-type receptors is nearby. To determine whether other receptor subunits also contribute to the blocker site, the hydrophobic mutagenesis strategy was extended to all four subunits at 10 ' loci. alpha S10 ' l causes the largest increase in apparent hexanol binding (4.3-fold compared to wild type), approximately twice the size of the change caused by beta T10 ' l (2.2-fold). gamma A10 ' l and delta A10 ' l mutations cause much smaller changes in apparent hexanol binding affinity (about 1.2-fold each), even when correctedfor their smaller degree of side-chain hydrophobicity changes. When 10 ' l mutant subunits are coexpressed, the change from wild type in apparent hexanol binding energy (Delta Delta G(mixture)) is roughly equal to the sum of hexanol binding energy changes for the constituent mutant subunits (Sigma Delta Delta G(subunits)). The simplest model consistent with these results is one in which hydrophobic blockers make simultaneous contact with all five M2 10 ' residues, but the extent of contact is much greater for the alpha and beta than for gamma and delta side chains.

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Documento generato il 30/09/20 alle ore 02:22:06