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Titolo:
POSITIVE COOPERATIVITY OF ACETYLCHOLINE AND OTHER AGONISTS WITH ALLOSTERIC LIGANDS ON MUSCARINIC ACETYLCHOLINE-RECEPTORS
Autore:
JAKUBIK J; BACAKOVA L; ELFAKAHANY EE; TUCEK S;
Indirizzi:
ACAD SCI CZECH REPUBL,INST PHYSIOL,VIDENSKA 1083 CR-14220 PRAGUE CZECH REPUBLIC ACAD SCI CZECH REPUBL,INST PHYSIOL CR-14220 PRAGUE CZECH REPUBLIC UNIV MINNESOTA,SCH MED MINNEAPOLIS MN 55455
Titolo Testata:
Molecular pharmacology
fascicolo: 1, volume: 52, anno: 1997,
pagine: 172 - 179
SICI:
0026-895X(1997)52:1<172:PCOAAO>2.0.ZU;2-0
Fonte:
ISI
Lingua:
ENG
Soggetto:
BINDING-PROPERTIES; ALCURONIUM; GALLAMINE; M(1); INACTIVATION; SELECTIVITY; XANOMELINE; SUBTYPE; CELLS; HEART;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
29
Recensione:
Indirizzi per estratti:
Citazione:
J. Jakubik et al., "POSITIVE COOPERATIVITY OF ACETYLCHOLINE AND OTHER AGONISTS WITH ALLOSTERIC LIGANDS ON MUSCARINIC ACETYLCHOLINE-RECEPTORS", Molecular pharmacology, 52(1), 1997, pp. 172-179

Abstract

It is well known that allosteric modulators of muscarinic acetylcholine receptors can both diminish and increase the affinity of receptors for their antagonists. We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric medulators were tested in experimentson membranes of CHO cells that had been stably transfected with genesfor the M-1-M-4 receptor subtypes. Allosterically induced changes in the affinities for agonists were computed from changes in the ability of a fixed concentration of each agonist to compete with [H-3]N-methylscopolamine for the binding to the receptors in the absence and the presence of varying concentrations of allosteric modulators. The effectsof allosteric modulators varied greatly depending on the agonists andthe subtypes of receptors. The affinity for acetylcholine was augmented by (-)-eburnamonine on the M-2 and M-4 receptors and by brucine on the M-1 and M-3 receptors. Brucine also enhanced the affinities for carbachol, bethanechol, furmethide, methylfurmethide, pilocarpine, 3-(3-pentylthio-1 ,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1 -methylpyridine (pentylthio-TZTP), oxotremorine-M, and McN-A-343 on the M-1, M-3, and M-4 receptors, for pentylthio-TZTP on the M-2 receptors, and for arecoline on the M-3 receptors. (-)-Eburnamonine enhanced the affinities for carbachol, bethanechol, furmethide, methylfurmethide, pentylthio-TZTP, pilocarpine, oxotremorine and oxotremorine-M on the M-2 receptorsand for pilocarpine on the M-4 receptors. Vincamine, strychnine, and alcuronium displayed fewer positive allosteric interactions with the agonists, but each allosteric modulator displayed positive cooperativity with at least one agonist on at least one muscarinic receptor subtype. The highest degrees of positive cooperativity were observed between(-)-eburnamonine and pilocarpine and (-)-eburnamonine and oxotremorine-M on the M-2 receptors (25- and 7-fold increases in affinity, respectively) and between brucine and pentylthio-TZTP on the M-2 and brucineand carbachol on the M-1 receptors (8-fold increases in affinity). The discovery that it is possible to increase the affinity of muscarinicreceptors for their agonists by allosteric modulators offers a new way to subtype-specific pharmacological enhancement of transmission at cholinergic (muscarinic) synapses.

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Documento generato il 06/04/20 alle ore 02:10:21