Activation of Endoplasmic Reticulum-Localized Metabotropic Glutamate Receptor 5 (mGlu5) Triggers Calcium Release Distinct from Cell Surface Counterparts in Striatal Neurons.

Metabotropic glutamate receptor 5 (mGlu5) plays a fundamental role in synaptic plasticity, potentially serving as a therapeutic target for various neurodevelopmental and psychiatric disorders. Previously, we have shown that mGlu5 can also signal from intracellular membranes in the cortex, hippocampus, and striatum. Using cytoplasmic Ca2+ indicators, we showed that activated cell surface mGlu5 induced a transient Ca2+ increase, whereas the activation of intracellular mGlu5 mediated a sustained Ca2+ elevation in striatal neurons. Here, we used the newly designed ER-targeted Ca2+ sensor, ER-GCaMP6-150, as a robust, specific approach to directly monitor mGlu5-mediated changes in ER Ca2+ itself. Using this sensor, we found that the activation of cell surface mGlu5 led to small declines in ER Ca2+, whereas the activation of ER-localized mGlu5 resulted in rapid, more pronounced changes. The latter could be blocked by the Gq inhibitor FR9000359, the PLC inhibitor U73122, as well as IP3 and ryanodine receptor blockers. These data demonstrate that like cell surface and nuclear mGlu5, ER-localized receptors play a pivotal role in generating and shaping intracellular Ca2+ signals.