Fig. 8: States occupancies predictions and structural depiction of Model III.
From: The desensitization pathway of GABAA receptors, one subunit at a time
a The overall population of wild-type receptors in an active conformation is compared to the relative occupancies of the various desensitized states. As depicted by the red box, the early phase of desensitization is carried by the AD45 state. On longer timescales (blue box), slow desensitization is largely embodied by the entry in the AD345 state. The analysis of states occupancies was performed with QuB simulations. b In this simplified depiction of model III, we extracted the kinetically favored pathway for the desensitization of wild-type α1β2γ2 GABAARs. Upon agonist binding, the receptor is transiently stabilized in a fully open pseudo-symmetrical conformation. The two first subunits to rearrange during desensitization are the α1 and the γ2 subunits involved in the binding of benzodiazepines, namely SU4 and SU5 in our concatemers. While one desensitized subunit is not enough to occlude the pore, fast desensitization corresponds to the rearrangement of both SU4 and SU5 subunits, which are coupled. Slow desensitization is then driven by the slower rearrangement of the SU3 subunit, i.e. the β2 subunit opposite to the γ2 subunit.
