Voltage tunes mGlu₅ receptor function, impacting synaptic transmission

Background and Purpose Voltage sensitivity is a common feature of many membrane proteins, including some G‐protein coupled receptors (GPCRs). However, the functional consequences of voltage sensitivity in GPCRs are not well understood. Experimental approach In this study, we investigated the voltage sensitivity of the post‐synaptic metabotropic glutamate receptor mGlu 5 and its impact on synaptic transmission. Using biosensors and electrophysiological recordings in non‐excitable HEK293T cells or neurons. Key Results We found that mGlu 5 receptor function is optimal at resting membrane potentials. We observed that membrane depolarization significantly reduced mGlu 5 receptor activation, Gq‐PLC/PKC stimulation, Ca 2+ release and mGlu 5 receptor‐gated currents through transient receptor potential canonical, TRPC6, channels or glutamate ionotropic NMDA receptors. Notably, we report a previously unknown activity of the NMDA receptor at the resting potential of neurons, enabled by mGlu 5 . Conclusions and Implications Our findings suggest that mGlu 5 receptor activity is directly regulated by membrane voltage which may have a significant impact on synaptic processes and pathophysiological functions.