Affiliation:
1. Graduate School of Frontier Sciences, The University of Tokyo
2. National Institute of Advanced Industrial Science and Technology (AIST)
3. Ibaraki University
4. Japan Synchrotron Radiation Research Institute
Abstract
AbstractThe alpha 7 nicotinic acetylcholine receptor (nAChR α7) is composed of five α7 subunits arranged symmetrically around a central pore. nAChR α7 is localized in the central nervous system and immune cells and could be a target for treating Alzheimer’s disease and schizophrenia. Acetylcholine (ACh) is a ligand that opens the channel, although prolonged application results in a decrease in the response. Ivermectin (IVM) was reported as one of the positive allosteric modulators, since the binding of IVM to the channel enhances ACh-evoked alpha 7 currents. The molecular dynamics of the ligand-bound state of nAChR α7 have not been exhaustively studied. We utilized a diffracted X-ray tracking method to monitor the twisting and tilting motion of nAChR α7 without a ligand, with ACh, with IVM, and with both ACh and IVM (ACh_IVM). The results showed that nAChR α7 twisted counterclockwise with the channel opening in the presence of ACh and clockwise without the channel opening in the presence of IVM. The mechanism of channel opening may be due to the twisting of the five α7 subunits together, where one or more of them are squeezed and move downward or upward.
Publisher
Research Square Platform LLC