similar to natural fluctuations of membrane potential occurring at synapses.
In this study, we have demonstrated that a modest increase in membrane potential by approximately 20-25 mV is sufficient to reduce mGlu5 receptor activity by half. Our findings reveal that the mGlu5 receptor is highly sensitive to changes in membrane potential compared to other GPCRs which require stronger depolarizations, at least twice the level used in our study, and sometimes up to 140 mV, to induce a similar shift in receptor efficacy . Both patch clamp and KCl depolarization methods resulted in the same polarity of membrane potential effect on mGlu5 receptor function. Moreover, the effect of depolarization was comparable when applied before or during agonist perfusion, suggesting that membrane potential can either prevent optimal activation or rapidly reverse ongoing activation of the mGlu5 receptor. Notably, changes in dendritic spine membrane potential during post-synaptic potentials have been reported to be in the range of 20-25 mV, a magnitude similar to that observed in our study . Thus, local synaptic potentials may mediate rapid modulation of mGlu5 function in neurons. Although membrane potential changes were applied tonically in our study, similar results have been obtained by others using physiological frequency ranges, mimicking trains of action potentials . A more resolutive investigation would provide better insights into the intensity and duration of membrane potential variations required to modulate mGlu5 receptor activity and refine our understanding of the type of neuronal activity of similar magnitude and temporal order that could affect mGlu5 function.