Modeling the use of transient ligand binding information by AMPA receptors

Glutamate mediates fast excitatory neurotransmission through α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors in the central nervous system. Although it is well known that the glutamate affinity for AMPA receptors is submicromolar, ligand-dependent currents are observed only at submillimolar glutamate concentrations, suggesting a non-equilibrium mechanism of dose-dependent signaling. Here, we developed a mathematical model that leverages published reaction rates to demonstrate that AMPA receptors operate within a pre-equilibrium sensing and signaling (PRESS) regime. By functioning before equilibrium binding, AMPARs exploit a transient dynamic range at high ligand concentrations. Our model reveals that fast desensitization is a key transition enabling this PRESS mechanism. Regulators of this desensitization, such as transmembrane AMPAR regulatory proteins TARP, germ cell-specific gene 1-like protein and cornichon homolog auxiliary proteins (CNIH2/3), thus modulate AMPAR dynamic range by modifying the time window in which these receptors may use pre-equilibrium information. 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.