Ionotropic Glutamate Receptors & CNS Disorders

Abstract

Disorders of the central nervous system (CNS) are complex disease states that represent a major challenge for modern medicine. Although aetilogy is often unknown, it is established that multiple factors such as defects in genetics and/or epigenetics, the environment as well as imbalance in neurotransmitter receptor systems are all at play in determining an individual's susceptibility to disease. Gene therapy is currently not available and therefore, most conditions are treated with pharmacological agents that modify neurotransmitter receptor signaling. Here, I provide a review of ionotropic glutamate receptors (iGluRs) and the roles they fulfill in numerous CNS disorders. Specifically, I argue that our understanding of iGluRs has reached a critical turning point to permit, for the first time, a comprehensive re-evaluation of their role in the cause of disease. I illustrate this by highlighting how defects in AMPA receptor (AMPAR) trafficking are important to fragile X mental retardation and ectopic expression of kainate receptor (KAR) synapses contributes to the pathology of temporal lobe epilepsy. Finally, I discuss how parallel advances in studies of other neurotransmitter systems may allow pharmacologists to work towards a cure for many CNS disorders rather than developing drugs to treat their symptoms.

The Human Synaptic Vesicle Protein, SV2A, Functions as a Galactose Transporter in Saccharomyces cerevisiae

“…Abnormally enhanced glutamatergic neurotransmission is involved in the pathophysiology of epilepsy (24) and several neurodegenerative disorders, such as Parkinson disease, amyotrophic lateral sclerosis, Huntington disease, and Alzheimer disease (25,26). SV2A gained particular attention when it was identified as the binding site for the antiepileptic drug, levetiracetam (7).…”

Morphological, immunocytochemical, and functional characterization of esophageal enteric neurons in primary culture

“…These receptors include purinergic receptors, histamine receptors, 5-HTRs, AChR, and glutamate (NMDAR) (19). Most of them are GPCRs, the molecular and functional expression of which have been well documented in the central and enteric neurons (5,14,22,23,26,34). These neuronal receptors respond to neurotransmitters, such as ACh, ATP, histamine, 5-HT, and NMDA (19), and, importantly, these neurotransmitters signal through an increase in [Ca 2ϩ ] cyt , either by directly facilitating Ca 2ϩ influx through an ion channel or through the activation of GPCRs that couple to intracellular Ca 2ϩ stores or VGCC (13).…”

Ion channel therapeutics for pain

“…43 Subtypeselective GluN2B receptor antagonists in particular have attracted attention from the pharmaceutical research community for targeting CNS disorders including stroke and Parkinson disease. 44 Examples of GluN2B receptor antagonists include Ifenprodil 45 and the more selective derivative Traxoprodil 46 (Fig.…”