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Role of the extracellular transmembrane domain interface in gating and pharmacology of a heteromeric neuronal nicotinic receptor

AuthorsAldea, Marcos; Castillo, Mar; Mulet Soler, José; Sala, Salvador; Criado, Manuel ; Sala, Francisco
Issue Date2010
CitationJournal of Neurochemistry 113(4): 1036- 1045 (2010)
AbstractP>Nicotinic acetylcholine receptors (nAChRs) transmit the agonist signal to the channel gate through a number of extracellular domains. We have previously shown that particular details of the process of coupling binding to gating could be quantitative and qualitatively different in muscle and neuronal type nAChRs. We have extended previous studies on homomeric alpha 7 nAChRs to heteromeric alpha 3 beta 4 nAChRs, by mutating residues located at loops 2 and 7, and M2-M3 linker of both alpha 3 and beta 4 subunits which, in order to monitor surface expression, were modified to bind alpha-bungarotoxin, and expressed in Xenopus oocytes. We show that, in general, mutations in these domains of both alpha 3 and beta 4 subunits affect the gating function, although the effects are slightly larger if they are inserted in the alpha 3 subunit. However, the involvement of a previously reported intrasubunit interaction in coupling (Gln48-Ile130) seems to be restricted to the beta 4 subunit. We also show that mutations at these domains, particularly loop 2 of the alpha 3 subunit, change the pharmacological profile of alpha 3 beta 4 nAChRs, decreasing nicotine's and increasing cytisine's effectiveness relative to acetylcholine. It is concluded that, unlike muscle nAChRs, the non-alpha subunits play a relevant role in the coupling process of neuronal alpha 3 beta 4 nAChRs.
Identifiersdoi: 10.1111/j.1471-4159.2010.06665.x
issn: 0022-3042
e-issn: 1471-4159
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