Revisiting AMPA Receptors as an Antiepileptic Drug Target

Abstract

AMPA receptors are ion channels localized to excitatory synapses in the central nervous system that mediate fast (millisecond time scale) excitatory neurotransmission ( Fig. 1) (1). In excitatory neurons, action potentials evoke the release of glutamate from presynaptic terminals at synapses onto postsynaptic excitatory and inhibitory neurons. Synapses onto excitatory neurons are predominantly located on dendritic spines whereas excitatory synapses onto inhibitory interneurons are located on the aspiny dendritic shafts typical of these cells (2, 3). In either case, the glutamate released from the excitatory neuron axon terminals diffuses across the synaptic cleft and binds to AMPA receptors in the postsynaptic membrane. The AMPA receptors are large multisubunit protein complexes that span the membrane and have an ion-selective central pore that in the absence of glutamate is closed to ion flow. Binding of glutamate causes the AMPA receptors to gate open, which allows cations to flux across the postsynaptic membrane, resulting in a brief depolarization known as the excitatory postsynaptic potential (EPSP). Although AMPA receptors are permeable to sodium, potassium and in some cases also calcium, at resting potential sodium is the main carrier of the depolarizing current. Summation of EPSPs leads to the firing of action potentials by the postsynaptic neuron, completing the transmission of the synaptic signal. Given their role in fast excitatory signaling in the brain, AMPA receptors are a critical component of all neuronal networks. AMPA receptors are as fundamental to brain function as sodium channels but it is important to appreciate the distinction between the two. AMPA receptors mediate synaptic signaling whereas sodium channels are responsible for a neuron's intrinsic excitability. In line with their distinct functions, sodium channels are voltage-gated and they open in response to membrane depolarization. In contrast, AMPA receptors are largely insensitive to membrane potential; as neurotransmitter-gated channels, their opening is controlled by a chemical signal -glutamate, the universal chemical messenger for fast excitatory neurotransmission. The Architecture of AMPA ReceptorsThe cloning of the first AMPA receptor subunit in 1989 enabled the structural analysis of AMPA receptors and a detailed characterization of their physiology and pharmacology (4). It is now well established that there are four AMPA receptor subunits designated GluA1-GluA4 (formerly GluR1-GluR4), each encoded by a separate gene (5). The subunits have a modular organization (Fig. 2) (6, 7). There is a large extracellular aminoterminal domain that is involved in receptor assembly, trafficking and modulation; a ligand-binding domain that serves as the recognition site for agonists (including the natural agonist glutamate) and also represents the binding site for competitive antagonists; a transmembrane domain that forms the ion channel (consisting of three membrane-spanning hydrophobic domains and one intramembranous reentrant loop); and a...

Review of clinical studies of perampanel in adolescent patients

“…2011). AMPA receptor antagonists have a broad spectrum of anticonvulsant activity, being effective against fully kindled seizures (Rogawski 2011). …”

The Relationship between Glucose Metabolism, Resting-State fMRI BOLD Signal, and GABAA-Binding Potential: A Preliminary Study in Healthy Subjects and Those with Temporal Lobe Epilepsy

“…In the healthy brain, presynaptic metabotropic glutamate receptors regulate glutamate release via a negative feedback mechanism that results in neuronal inhibition; this inhibitory control mechanism-and thus the balance between excitation and inhibition-appears to be lost in TLE. 7 Positron emission tomography (PET) has been used extensively to examine the physiology of seizure foci. PET studies using the ligand [ 11 C]-flumazenil, a GABA A receptor antagonist, have consistently found decreased binding in hippocampus ipsilateral to seizure foci, [8][9][10][11] particularly in patients exhibiting atrophy or mesial temporal sclerosis.…”

Perampanel: Getting AMPed for AMPA Targets

“…These receptors are known as AMPA, kainate, and NMDA (2). Perampanel is the first agent of its kind to target the AMPA receptor (1)(2)(3)(4)(5). Thus, the positive study results from this trial affirm this molecular approach to tackling seizures with expectations for other drugs similarly designed.…”