Fig. 8. Dual advantage of enhancing KCC2: L838,417 potency and efficacy improvement.
a Computer simulations predicting a collapse in anionic current when inhibitory conductance (ginh) is increased beyond an optimal value (black curve, see methods). When an increase of 40% in the strength of Cl− extrusion through KCC2 was simulated, the collapse in anionic current for large inhibitory conductance was prevented (red curve as in Fig. 4e). b Experimental MPA (maximum possible analgesia) with L838,417 (black empty dots) was fitted with a Hill equation (black curve) where the last data point was ignored (which correspond to a decline in analgesia). To better describe the collapse in inhibition occurring at high L838,417 doses, two independent processes were combined to generate the final fitting function. The fitting function (purple curve, Eq. 4) that takes into account the collapse consists of the product of a normal dose-response curve (Eq. 2) without collapse (dashed red curve with amplitude set to the value obtained in Fig. 6g) and an inverse normalized dose-response curve representing the collapse (dashed blue curve). Combining the two independent processes in a single fitting function (purple curve) yielded a better global fit of the experimental MPA with L838,417 than a simple Hill fit (black curve). c A schematic representation of how CLP257 and L838,417 synergistically act on net inhibition. L838,417 increases anionic conductance while CLP257 favors Cl− extrusion via KCC2. This, in turns interacts to determine the value of Cl− reversal potential as well as the net anionic current which promotes analgesia155. F is the Faraday constant, J denotes a flux and U is a proportionality constant capturing the strength of KCC2 activity (see Methods). Source data is available as a Source Data file.