Calcium Permeable-AMPA Receptors and Excitotoxicity in Neurological Disorders

Abstract

Excitotoxicity is one of the primary mechanisms of cell loss in a variety of diseases of the central and peripheral nervous systems. Other than the previously established signaling pathways of excitotoxicity, which depend on the excessive release of glutamate from axon terminals or over-activation of NMDA receptors (NMDARs), Ca2+ influx-triggered excitotoxicity through Ca2+-permeable (CP)-AMPA receptors (AMPARs) is detected in multiple disease models. In this review, both acute brain insults (e.g., brain trauma or spinal cord injury, ischemia) and chronic neurological disorders, including Epilepsy/Seizures, Huntington’s disease (HD), Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), chronic pain, and glaucoma, are discussed regarding the CP-AMPAR-mediated excitotoxicity. Considering the low expression or absence of CP-AMPARs in most cells, specific manipulation of the CP-AMPARs might be a more plausible strategy to delay the onset and progression of pathological alterations with fewer side effects than blocking NMDARs.

Extracellular Calcium Influx Pathways in Astrocyte Calcium Microdomain Physiology

“…Based on their selective agonists, iGluRs are categorized into three classes, including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, kainate receptors, and N-methyl-D-aspartate (NMDA) receptors [97]. AMPA receptors are tetramers formed from four possible subunits (GluA1-GluA4), which dictate the functional properties of the receptor, including their calcium permeability [98]. These receptors also generally have rapid deactivation kinetics [99].…”

Insertion of Calcium-Permeable AMPA Receptors during Epileptiform Activity In Vitro Modulates Excitability of Principal Neurons in the Rat Entorhinal Cortex

“…Our results demonstrate that the blocking of CP-AMPARs by N,N,N-trimethyl-5-[(tricyclo [3.3.1.1 3,7 ]dec-1-ylmethyl)amino]-1-pentanaminium bromide hydrobromide (IEM-1460) augments the epileptiform activity through a decrease in membrane input conductance. We clarify the contribution of activity-dependent shunting conductance into discharge generation using a mathematical model.…”

“…Such abnormal expression is usually considered pathological because it can contribute to calcium-dependent cell loss after seizures and the development of acquired epilepsy. Some studies even propose the CP-AMPARs as a therapeutic target [3,23,71,72].…”

“…AMPARs are tetrameric complexes of four subunits (GluA1-GluA4) [1]. The subunit composition of AMPARs determines their functional properties, trafficking, synaptic localization, interaction with intracellular proteins, and Ca 2+ permeability [2,3]. For example, a lack of GluA2 subunit or the presence of an unedited GluA2 subunit in the receptor complex renders the AMPAR to be permeable to calcium ions [4].…”

Phenylalanine-Based AMPA Receptor Antagonist as the Anticonvulsant Agent with Neuroprotective Activity—In Vitro and In Vivo Studies

“…Among several signaling pathways controlling excitotoxicity, which are due to the excessive release of glutamate from axon terminals or overactivation of NMDA receptors, Ca 2+ influx-triggered excitotoxicity through AMPA receptors has been demonstrated in multiple disease models. These AMPA receptor-dependent phenomena are regarded as significant contributors to both acute brain injuries and chronic neurological disorders, such as epilepsy, neurodegenerative disorders (Huntington’s disease, PD, AD, ALS), chronic pain, and many others [ 23 ]. Since the in vivo part of the present research was the first-in-animal study and also considering that in vitro neuroprotective properties of compound 1 were assessed, we focused on in vivo assays to evaluate the compound 1 in animal models and tests that reflect disorders for which AMPA receptor antagonists seem to be particularly promising drug candidates, namely epilepsy [ 10 , 24 ] and pain [ 25 , 26 , 27 ].…”