Résumé
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.