Activation of Endoplasmic Reticulum-Localized Metabotropic Glutamate Receptor 5 (mGlu<sub>5</sub>) Triggers Calcium Release Distinct from Cell Surface Counterparts in Striatal Neurons
Metabotropic glutamate receptor 5 (mGlu<sub>5</sub>) plays a fundamental role in synaptic plasticity, potentially serving as a therapeutic target for various neurodevelopmental and psychiatric disorders. Previously, we have shown that mGlu<sub>5</sub> can also signal from int...
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| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-04-01
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| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/15/4/552 |
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| Summary: | Metabotropic glutamate receptor 5 (mGlu<sub>5</sub>) plays a fundamental role in synaptic plasticity, potentially serving as a therapeutic target for various neurodevelopmental and psychiatric disorders. Previously, we have shown that mGlu<sub>5</sub> can also signal from intracellular membranes in the cortex, hippocampus, and striatum. Using cytoplasmic Ca<sup>2+</sup> indicators, we showed that activated cell surface mGlu<sub>5</sub> induced a transient Ca<sup>2+</sup> increase, whereas the activation of intracellular mGlu<sub>5</sub> mediated a sustained Ca<sup>2+</sup> elevation in striatal neurons. Here, we used the newly designed ER-targeted Ca<sup>2+</sup> sensor, ER-GCaMP6-150, as a robust, specific approach to directly monitor mGlu<sub>5</sub>-mediated changes in ER Ca<sup>2+</sup> itself. Using this sensor, we found that the activation of cell surface mGlu<sub>5</sub> led to small declines in ER Ca<sup>2+</sup>, whereas the activation of ER-localized mGlu<sub>5</sub> resulted in rapid, more pronounced changes. The latter could be blocked by the Gq inhibitor FR9000359, the PLC inhibitor U73122, as well as IP<sub>3</sub> and ryanodine receptor blockers. These data demonstrate that like cell surface and nuclear mGlu<sub>5</sub>, ER-localized receptors play a pivotal role in generating and shaping intracellular Ca<sup>2+</sup> signals. |
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| ISSN: | 2218-273X |