Location and Cell-Type-Specific Bias of Metabotropic Glutamate Receptor, mGlu5, Negative Allosteric Modulators
Year: 2019
Type: article
Abstract: Emerging data indicate that G-protein coupled receptor (GPCR) signaling is determined by not only the agonist and a given receptor but also a variety of cell-type-specific factors that can influence a receptor’s response. For example, the metabotropic glutamate receptor, mGlu 5, which is implicated in a number of neuropsychiatric disorders such as depression, anxiety, and autism, also signals from inside the cell which leads to sustained Ca 2+ mobilization versus rapid transient responses. Because mGlu 5 is an important drug target, many negative allosteric modulators (NAMs) have been generated to modulate its activity. Here we show that NAMs such as AFQ056, AZD2066, and RG7090 elicit very different end points when tested in postnatal neuronal cultures expressing endogenous mGlu 5 receptors. For example, AFQ056 fails to block intracellular mGlu 5 -mediated Ca 2+ increases whereas RG7090 is very effective. These differences are not due to differential receptor levels, since about the same number of mGlu 5 receptors are present on neurons from the cortex, hippocampus, and striatum based on pharmacological, biochemical, and molecular data. Moreover, biotinylation studies reveal that more than 90% of the receptor is intracellular in these neurons. Taken together, these data indicate that the tested NAMs exhibit both location-dependent and cell type specific bias for mGlu 5 -mediated Ca 2+ mobilization which may affect clinical outcomes.
Source: ACS Chemical Neuroscience
Institution: Washington University in St. Louis
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Awards: LOCATION-DEPENDENT SIGNALING OF MGLU5 IN MODELS OF SYNAPTIC PLASTICITY USING CRISPR-TARGETED MICE, SELECTIVE ACTIONS OF MGLU5 RECEPTOR NEGATIVE ALLOSTERIC MODULATORS, WASHINGTON UNIVERSITY INTELLECTUAL AND DEVELOPMENTAL DISABILITIES RESEARCH CENTER, Expanding Access to Planar Illumination Microscopy in a Neuroimaging Core, Testing the role of intracellular vs. cell surface mGlu5 in models of synaptic plasticity using CRISPR-modified mice, G7860800203
OpenAlex ID: W2981263508