Back Action on Neurotransmitters by Receptor Binding Reveals an Optimal Receptor Density Profile

Abstract

We discuss how integration of back action into coupled rate equations describing dynamical biophysical processes can to lead the identification of optimized structural features. This approach is applied to analyze neural receptor binding and function. In functional receptor studies, the influence of ligand binding to the receptor on free ligand concentration in the synaptic cleft is rarely considered, especially when the number of ligand molecules vastly exceeds the number of receptors. Here we evaluate the role of ligand binding/unbinding to the receptor on ligand concentration and the resulting change in receptor dynamics using the example of glutamate interaction with the AMPA receptor subtype of glutamate receptors. We find a significant difference for AMPA receptor-mediated current between the free diffusion case, where binding/unbinding is neglected, and the case when glutamate binding to AMPA receptors is taken into account for evaluating free ligand concentration. Furthermore, taking into account receptor binding/unbinding reveals new properties of the receptor/neurotransmitter system, and in particular, indicates the existence of an optimum receptor density profile with an optimal radius where the total charge and peak current are maximal, a property that cannot be captured by the free diffusion case. This may provide an explanation for the disposition of AMPA receptors and the synaptic geometry based on the optimization of the receptor-mediated current.