Why Is α4β2 Nachr More Sensitive to Volatile Anesthetics Than α7 Nachr?

Abstract

Two subtypes of neuronal nicotinic acetylcholine receptors (nAChRs) show different functional sensitivities to volatile anesthetics: the α4β2 nAChR is hypersensitive while the α7 nAChR is insensitive. To understand why these homologous proteins have different functional responses to volatile anesthetics, we performed multiple sets of 20-ns molecular dynamics (MD) simulations on the closed- and open-channel α7 in the absence and presence of halothane, and compared the results with those from a similar study on the α4β2 nAChR (Liu, et al. 2009). The details about construction of receptor structural models were published (Haddadian, et al. 2008). Initial halothane docking and subsequent MD simulations revealed several halothane-binding sites in α7. Consistent with observations from α4β2, free energy perturbation calculations showed that halothane had higher binding affinity in the closed- than the open-channel; α7 and α4β2 had a comparable number of high affinity sites. GNM analysis showed that halothane induced profound changes in correlated domain motion of the open-channel α4β2, especially between the Cys-loop and the TM2-TM3 linker, but had a negligible impact to the motion of the α7. Salt bridges between these loops in the β2 subunit may be responsible for the aforementioned observation. Flexibility of several key loops in the open-channel α4β2 changed considerably in the presence of halothane, but the same loops in the open-channel α7 showed little change. Taken together, our results suggest that halothane binding in nAChRs may be necessary, but not sufficient to produce essential dynamical changes that alter protein functions. Although α7 and α4β2 are homologous, specific residues in key loops may make α4β2 more susceptible to volatile anesthetics while α7 unaffected. Supported by NIH (R01GM66358, R01GM56257, and T32GM075770) and NCSA through the PSC.