Insights into distinct modulation of ?7 and ?7?2 nicotinic acetylcholine receptors by the volatile anesthetic isoflurane.

ABSTRACT: Nicotinic acetylcholine receptors (nAChRs) are targets of general anesthetics, but functional sensitivity to anesthetic inhibition varies dramatically among different subtypes of nAChRs. Potential causes underlying different functional responses to anesthetics remain elusive. Here we show that in contrast to the ?7 nAChR, the ?7?2 nAChR is highly susceptible to inhibition by the volatile anesthetic isoflurane in electrophysiology measurements. Isoflurane-binding sites in ?2 and ?7 were found at the extracellular and intracellular end of their respective transmembrane domains using NMR. Functional relevance of the identified ?2 site was validated via point mutations and subsequent functional measurements. Consistent with their functional responses to isoflurane, ?2 but not ?7 showed pronounced dynamics changes, particularly for the channel gate residue Leu-249(9'). These results suggest that anesthetic binding alone is not sufficient to generate functional impact; only those sites that can modulate channel dynamics upon anesthetic binding will produce functional effects.

SUBMITTER: Mowrey DD 

PROVIDER: S-EPMC3861630 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature