TY - JOUR
T1 - Location and Cell-Type-Specific Bias of Metabotropic Glutamate Receptor, mGlu5, Negative Allosteric Modulators
AU - Jong, Yuh Jiin Ivy
AU - Harmon, Steven K.
AU - O'Malley, Karen L.
N1 - Funding Information:
Y.I.J. and K.L.O. designed the study and wrote the paper. S.K.H. prepared the primary cultures. Y.I.J. carried out the experiments and analyzed the data. All authors reviewed the results and approved the final version of the manuscript. This work was supported, in whole or in part, by National Institutes of Health Grants MH109019 and NS102783, IDDRC Grant #U54 HD087011, and the Lilly Research Award Program. The authors declare no competing financial interest.
Funding Information:
We thank Dr. David L. McKinzie (Lilly USA) for reagents and advice. We also thank Dr. Ron Dolle (Washington University in St. Louis) for helpful discussions and critical reading of the manuscript. Microscopes and software were provided in part through the use of Washington University Center for Cellular Imaging (WUCCI) supported by Washington University School of Medicine, The Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (CDI-CORE-2015-505), and the NINDS, National Institutes of Health (NS086741).
Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2019/11/20
Y1 - 2019/11/20
N2 - 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, mGlu5, 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 Ca2+ mobilization versus rapid transient responses. Because mGlu5 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 mGlu5 receptors. For example, AFQ056 fails to block intracellular mGlu5-mediated Ca2+ increases whereas RG7090 is very effective. These differences are not due to differential receptor levels, since about the same number of mGlu5 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 mGlu5-mediated Ca2+ mobilization which may affect clinical outcomes.
AB - 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, mGlu5, 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 Ca2+ mobilization versus rapid transient responses. Because mGlu5 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 mGlu5 receptors. For example, AFQ056 fails to block intracellular mGlu5-mediated Ca2+ increases whereas RG7090 is very effective. These differences are not due to differential receptor levels, since about the same number of mGlu5 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 mGlu5-mediated Ca2+ mobilization which may affect clinical outcomes.
KW - GPCR
KW - NAM
KW - calcium
KW - intracellular
KW - mGlu
KW - neuron
UR - http://www.scopus.com/inward/record.url?scp=85074423036&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.9b00415
DO - 10.1021/acschemneuro.9b00415
M3 - Article
C2 - 31609579
AN - SCOPUS:85074423036
SN - 1948-7193
VL - 10
SP - 4558
EP - 4570
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 11
ER -