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.