Fig. 9. Model for asymmetric activation of 5HT₃R.

Proposed model for allosterically lipid-modulated asymmetric activation of 5HT₃R upon serotonin binding, based on 5HT₃R-Salipro structures, MD, and previous observations from single-channel recordings²⁹. Various degrees of mean channel open times have been observed in response to different numbers of consecutive/non-consecutive ligands bound²⁹. We speculate that the asymmetric apo form represents an intermediate state; that asymmetric opening may result from sequential ligand binding (5-HT shown in red) via this state yielding sequential conformational changes stabilised by the introduction of inter-subunit lipids (shown in light blue) during the transition of each subunit from a resting to an activated conformation; and that, considering that the channel already shows maximal mean open times upon binding three non-consecutive ligands²⁹, one ligand-binding event results in the introduction of two inter-subunit lipids as depicted (adjacent to the principal and the complementary ligand-binding subunits), thus resulting in stabilisation of the open state by five lipids upon binding of three non-consecutive ligands. Light blue, light grey and dark blue pentamers correspond to the resolved apo-C5, apo-C1 and serotonin-bound 5HT₃R-Salipro conformations, and dark grey pentamers to various unresolved asymmetric conformations with partial ligand occupancy.