Presynaptic AMPA Receptors in Health and Disease

Abstract

AMPA receptors (AMPARs) are ionotropic glutamate receptors that play a major role in excitatory neurotransmission. AMPARs are located at both presynaptic and postsynaptic plasma membranes. A huge number of studies investigated the role of postsynaptic AMPARs in the normal and abnormal functioning of the mammalian central nervous system (CNS). These studies highlighted that changes in the functional properties or abundance of postsynaptic AMPARs are major mechanisms underlying synaptic plasticity phenomena, providing molecular explanations for the processes of learning and memory. Conversely, the role of AMPARs at presynaptic terminals is as yet poorly clarified. Accruing evidence demonstrates that presynaptic AMPARs can modulate the release of various neurotransmitters. Recent studies also suggest that presynaptic AMPARs may possess double ionotropic-metabotropic features and that they are involved in the local regulation of actin dynamics in both dendritic and axonal compartments. In addition, evidence suggests a key role of presynaptic AMPARs in axonal pathology, in regulation of pain transmission and in the physiology of the auditory system. Thus, it appears that presynaptic AMPARs play an important modulatory role in nerve terminal activity, making them attractive as novel pharmacological targets for a variety of pathological conditions.

How Do Modulators Affect the Orthosteric and Allosteric Binding Pockets?

“…All of these targets play important roles in the nervous system. For example, the β2 adrenergic receptor belongs to the sympathetic nervous system, , glucokinase (GK) gets involved in the neuronal glucose-sensing mechanism, , and ionotropic glutamate receptors, such as AMPA and NMDA receptor (NMDAR), modulate neuronal excitability with the excitatory neurotransmitter, glutamate. − Exploiting our innovative technique, MCCS, we investigated whether the binding of a modulator had an impact on the orthosteric ligand binding via systematically comparing the 3D structure of receptor–ligand with and without a modulator, which would highly facilitate the rational design and development of modulator drug candidates.…”

Anti-AMPA Receptor Autoantibodies Reduce Excitatory Currents in Rat Hippocampal Neurons

“…Overall, we propose an inhibitory anti-AMPAR Aab effects which occur via a predominantly presynaptic action to reduce glutamate release and/or receptor internalization ( Figure 6 ). The presence of presynaptically expressed GluR3 subunits in the hippocampus is now well documented, as is their potential contribution to pathophysiology [ 31 ]; thus, Zanetti et al review several reports whereby GluR3, assembled with GluR2, make important contribution to presynaptic function, including transmitter release and receptor trafficking [ 31 ]. It is well known that AMPARs play an important role in synaptic plasticity and, in particular, expression on postsynaptic dendritic spines is a dynamic, activity-dependent process, which is regulated by distinct subunit composition and post-translational modifications [ 8 ].…”

Glutamatergic system components as potential biomarkers and therapeutic targets in cancer in non-neural organs

“…AMPA receptors evoke excitatory postsynaptic potentials and mediate the fast signal transmission of glutamate and receptor turnover in the CNS ( 27 , 34 ). They are also involved in synaptic plasticity, which forms the basis of learning and memory, and display rapid desensitization ( 34 ).…”

“…AMPA receptors evoke excitatory postsynaptic potentials and mediate the fast signal transmission of glutamate and receptor turnover in the CNS ( 27 , 34 ). They are also involved in synaptic plasticity, which forms the basis of learning and memory, and display rapid desensitization ( 34 ). Posttranscriptional modifications make AMPA receptor subtypes that form homo and heterotetrameric channels highly diverse ( 35 , 36 ) A specialized set of auxiliary proteins interacts with these receptors providing functional regulation ( 37 ).…”