Published: 10 March 2023| Version 1 | DOI: 10.17632/nhzxgw23m4.1
Helena Braunstein, Alejandra Ventura, Alejandro Colman-Lerner


Glutamate mediates fast excitatory neurotransmission by the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors in the central nervous system (CNS). It has long been shown that glutamate affinity for AMPA receptors is submicromolar but the concentrations of glutamate required to elicit ligand-dependent currents are, depending on exact subunit composition, in the submillimolar range. How is it that glutamate may exert dose-dependent responses in a concentration range at which AMPA receptors are largely saturated, has remained unexplained. Here, we employed a mathematical modeling approach using published reaction rates to show that AMPARs operate in a pre-equilibrium sensing and signaling (PRESS) regime. By operating before equilibrium binding, AMPARs exploit a transient dynamic range shifted to high ligand concentrations. We also show that the key transition enabling PRESS is the fast desensitization step, and that natural regulators of this step, such as transmembrane AMPA-R regulatory proteins, modulate AMPARs dynamic range by modifying the location of the usable transient dose-dependent response region. We speculate that the use of PRESS by AMPARs helps restrict the postsynaptic area of action of this fast transmission. Other receptors with fast desensitization may also take advantage of PRESS to accurately control dose-dependent responses. The data provided includes models in COPASI's .cps format, simulated datasets, and an .RMD file to reproduce the paper's figures.



Neuroscience, Systems Biology