Use of pre-equilibrium information by AMPA glutamatergic receptors

Abstract 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. It has long been shown that glutamate affinity for AMPA receptors is submicromolar. However, the concentrations of glutamate required to elicit ligand-dependent currents are at up to five hundred-fold higher, 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 that shows 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, and we propose that natural regulators of this step, such as transmembrane AMPAR regulatory proteins, would modulate AMPARs dynamic range by modifying the time window in which AMPARs 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.