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Parkinson’s disease, epilepsy, and amyotrophic lateral sclerosis—emerging role of AMPA and kainate subtypes of ionotropic glutamate receptors

Published on 10.24.2023 in Frontiers in Cell and Developmental Biology


Marina N. Vukolova, Laura Y. Yen, Margarita I. Khmyz, Alexander I. Sobolevsky and Maria V. Yelshanskaya

Ionotropic glutamate receptors (iGluRs) play a crucial role in mediating the majority of excitatory neurotransmission within the central nervous system. These receptors are widely distributed throughout the brain and are implicated in various neurological disorders. In this comprehensive review, we will delve deeper into the significance of two distinct subtypes of iGluRs: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and kainate receptors.

Excitatory neurotransmission is essential for normal brain function, as it facilitates communication between neurons and enables processes such as learning, memory formation, and synaptic plasticity. However, aberrant activation or dysfunction of iGluRs can contribute to the pathogenesis of neurodegenerative diseases and epileptic disorders, such as Parkinson’s disease, epilepsy, and amyotrophic lateral sclerosis. Understanding the intricate mechanisms underlying the role of AMPA and kainate receptors in these conditions is crucial for the development of targeted therapeutic interventions.

Parkinson’s disease is a progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra, leading to motor impairments. While the primary pathology of Parkinson’s disease lies within the dopaminergic system, emerging evidence suggests a potential role for glutamatergic dysfunction, including alterations in AMPA and kainate receptor expression and signaling. Further investigation into the interplay between glutamatergic neurotransmission and dopaminergic pathways may shed light on novel therapeutic approaches for this complex disorder.

Epilepsy, on the other hand, is a neurological condition characterized by recurrent seizures. Glutamate is the principal excitatory neurotransmitter in the brain, and dysregulation of glutamatergic signaling has been implicated in seizure generation and propagation. AMPA and kainate receptors, which mediate fast excitatory transmission, are thought to be involved in the initiation and maintenance of seizures. Targeting these receptors with specific modulators may offer potential avenues for the development of new antiepileptic drugs.

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a devastating neurodegenerative disorder that affects motor neurons. Glutamate-mediated excitotoxicity, resulting from an imbalance between glutamate release and removal, is considered a major contributing factor to the degeneration of motor neurons in ALS. Dysregulation of AMPA and kainate receptor function has been observed in both familial and sporadic forms of ALS, highlighting their potential involvement in disease progression. Exploring the underlying mechanisms and developing strategies to modulate glutamatergic neurotransmission could lead to novel therapeutic approaches in the treatment of ALS.

In summary, it is evident that AMPA and kainate receptors play significant roles in the pathogenesis of Parkinson’s disease, epilepsy, and amyotrophic lateral sclerosis.

Although both AMPA and kainate receptors represent promising therapeutic targets for the treatment of these diseases, many of their antagonists show adverse side effects. These receptors are emerging as potential targets for therapeutic interventions in these neurological disorders. Further research is needed to deepen our understanding of the intricate molecular mechanisms associated with iGluR dysfunction, which will pave the way for the development of effective treatments aimed at restoring normal glutamatergic neurotransmission and ameliorating the devastating effects of these diseases.