Discussion
In this study, we demonstrate that the activity and signaling of the mGlu5 receptor is influenced by the membrane potential of the cell, highlighting an aspect of the receptor that has previously been overlooked. Specifically, a depolarization of the membrane promotes an inactive-like conformation of the receptor, a reduction in mGlu5 coupling to Gq/11 and subsequent release of Ca2+ from intracellular stores. This results in a reduced activation of downstream effectors, including TRPC6 channels and ionotropic NMDA receptors. The mGlu5 receptor is a critical component in the modulation of synaptic transmission, and it plays a role in both inducing and regulating Hebbian and homeostatic synaptic plasticity processes. As such, the sensitivity of the mGlu5 receptor to membrane potential will impact its functions, and its role may vary depending on the context of neuronal activity.