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.