Mode of action of the positive modulator PNU-120596 on alpha7 nicotinic acetylcholine receptors.
  • Metaadatok
Tartalom: http://real.mtak.hu/11266/
Archívum: MTA Könyvtár
Gyűjtemény: Status = Published

Type = Article
Cím:
Mode of action of the positive modulator PNU-120596 on alpha7 nicotinic acetylcholine receptors.
Létrehozó:
Szabó, A. K.
Pesti, Krisztina
Mike, Árpád
Vizi, E. Szilveszter
Dátum:
2014
Téma:
RM Therapeutics. Pharmacology / terápia, gyógyszertan
Tartalmi leírás:
We investigated the mode of action of PNU-120596, a type II positive allosteric modulator of the rat alpha7 nicotinic acetylcholine receptor expressed by GH4C1 cells, using patch-clamp and fast solution exchange. We made two important observations: first, while PNU-120596 rapidly associated to desensitized receptors, it had at least hundredfold lower affinity to resting conformation, therefore at 10 muM concentration it dissociated from resting receptors; and second, binding of PNU-120596 slowed down dissociation of choline molecules from the receptor radically. We propose that when agonist concentration is transiently elevated in the continuous presence of the modulator (as upon the neuronal release of acetylcholine in a modulator-treated animal) these two elements together cause occurrence of a cycle of events: Binding of the modulator is limited in the absence of the agonist. When the agonist is released, it binds to the receptor, and induces desensitization, thereby enabling modulator binding. Modulator binding in turn traps the agonist within its binding site for a prolonged period of time. Once the agonist finally dissociated, the modulator can also dissociate without re-binding, and the receptor assumes its original resting conformation. In kinetic simulations this "trapped agonist cycle" mechanism did not require that the orthosteric and allosteric ligands symmetrically modify each other's affinity, only the modulator must decrease agonist accessibility, and the agonist must induce a conformation that is accessible to the modulator. This mechanism effectively prolongs and amplifies the effect of the agonist.
Típus:
Article
PeerReviewed
Formátum:
text
Azonosító:
Szabó, A. K. and Pesti, Krisztina and Mike, Árpád and Vizi, E. Szilveszter (2014) Mode of action of the positive modulator PNU-120596 on alpha7 nicotinic acetylcholine receptors. NEUROPHARMACOLOGY, 81C. pp. 42-54. ISSN 0028-3908
Kapcsolat: