Voltage tunes mGlu 5 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.
(© 2024 British Pharmacological Society.)