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.
Highlights
Excitotoxicity is one of the primary mechanisms of cell death in a variety of diseases of the central and peripheral nervous systems (CNS and PNS; Plotegher et al, 2021)
In addition to a general overview of mechanisms leading to upregulation of CP-AMPA receptors (AMPARs), both the effects of acute brain insults 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 reviewed
It was hypothesized that this rearrangement of C-terminal intracellular domain (CTD) binding proteins results in, first, disruption of AMPAR clusters at the synaptic membrane, second, internalization of synaptic GluA2 subunits, and third, restraint of GluA2 subunits to the intracellular pool in the ER (Figure 4)
Summary
Excitotoxicity is one of the primary mechanisms of cell death in a variety of diseases of the central and peripheral nervous systems (CNS and PNS; Plotegher et al, 2021). The non-NMDA excitatory receptors, including AMPA/Kainate receptors, have been generally considered as Ca2+ impermeable based on the fact that the estimated Ca2+ permeability of non-NMDARs is about 100-fold lower than that of NMDARs (Mayer and Westbrook, 1987). The role of CP-AMPARs in physiological and pathological conditions has been studied extensively. Particular emphasis is placed on the role of CP-AMPARs in excitotoxicity, which is. A few recent reviews discussed the potential roles of CP-AMPARs in brain diseases (Kwak and Weiss, 2006; Wright and Vissel, 2012), the present review covers a number of neural mechanisms related to RNA editing and other regulations at the transcriptional and post-translational levels. In addition to a general overview of mechanisms leading to upregulation of CP-AMPARs, both the effects of 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 reviewed
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