Glutamate-Related Biomarkers in Drug Development for Disorders of the Nervous System Workshop Summary (2011) / Chapter Skim
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2 Overview of the Glutamatergic System
2 Overview of the Glutamatergic System
Pages 5-10
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From page 5... ...
At least 30 proteins at, or near, the glutamate synapse control or modulate neuronal excitability, noted Darryle Schoepp, senior vice president of neuroscience at Merck. These proteins are membrane-bound receptor or transporter proteins (Figure 2-1)
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From page 6... ...
. The complexity of regulating glutamate and its pervasive presence throughout the brain may explain why, over the past decades, only three prescription medications have been developed that specifically target glutamate or glutamate receptors, memantine, ketamine, and D-cylcoserine.
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In terms of drug development, the goal is to carefully select a molecular target that modulates dysfunctional glutamate pathways, without disruption of healthy pathways, and minimizes adverse effects. That challenge to glutamate diagnostics and therapeutics was clearly articulated at the outset of the workshop by presenters Schoepp and Dan Javitt, program director in cognitive neuroscience and schizophrenia at the Nathan Kline Institute for Psychiatric Research: • H ow can glutamatergic synaptic transmission be selectively modu lated in the central nervous system?
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From page 8... ...
GluR2, otherwise moderate; short channel open time GluR5* , GluR6, GluR7, Kainate receptor Homotetrameric or KA1, and KA2 heterotetrameric; calcium permeability low; short channel open time Metabotropic Receptors mGluR1*
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From page 9... ...
The activation of the protein also triggers functional changes in the cytoplasm, culminating in gene expression and protein synthesis. There are three broad groups of glutamate metabotropic receptors, distinguished by their pharmacological and signal transduction properties.
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From page 10... ...
. Given the number of receptors and transporters, the range of cell types expressing them, the variety of regulatory controls, and the narrow concentration difference between normal synaptic function and excitotoxicity, many fundamental questions remain about how to choose potential pharmacological targets.
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