Unresponsive Correlated Motion in α7 nAChR to Halothane Binding Explains Its Functional Insensitivity to Volatile Anesthetics

Neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated as targets for general anesthetics, but the functional responses to anesthetic modulation vary considerably among different subtypes of nAChRs. Inhaled general anesthetics, such as halothane, could effectively inhibit the channel activity of the alpha 4 beta 2 nAChR but not the homologous alpha 7 nAChR. To understand why alpha 7 is insensitive to inhaled general anesthetics, we performed multiple sets of 20 ns molecular dynamics (MD) simulations on the closed- and open-channel alpha 7 in the absence and presence of halothane and critically compared the results with those from our studies on the alpha 4 beta 2 nAChR (Liu et al. J. Phys. Chem. B 2009, 113, 12581 and Liu et al. J. Phys. Chem. B 2010, 114, 626). Several halothane binding sites with fairly high binding affinities were identified in both closed- and open-channel alpha 7, suggesting that a lack of sensitive functional responses of the alpha 7 nAChR to halothane in the previous experiments was unlikely due to a lack of halothane interaction with alpha 7. The binding affinities of halothane in alpha 7 seemed to be protein conformation-dependent. Overall, halothane affinity was higher in the closed-channel alpha 7. Halothane binding to alpha 7 did not induce profound changes in alpha 7 structure and dynamics that could be related to the channel function. In contrast, correlated motion of the open-channel alpha 4 beta 2 was reduced substantially in the presence of halothane, primarily clue to the more susceptible nature of beta 2 to anesthetic modulation. The amphiphilic extracellular and transmembrane domain interface of the beta 2 subunit is attractive to halothane and is susceptible to halothane perturbation, which may be why alpha 4 beta 2 is functionally more sensitive to halothane than alpha 7.