G protein-coupled receptors mobilize neuronal signaling cascades which until now have not been shown to depend on the state of membrane depolarization. Thus we have previously shown that the metabotropic glutamate receptor type 7 (mGlu7 receptor) blocks P/Q-type Ca2+ channels via activation of a Go protein and PKC, in cerebellar granule cells. We show here that the transient depolarizations used to evoke the studied Ca2+ current were indeed permissive to activate this pathway by a mGlu7 receptor agonist. Indeed, sustained depolarization to 0 mV was sufficient to inhibit P/Q-type Ca2+ channels. This effect involved a conformational change in voltage-gated sodium channel (VGSC) independently of Na+ flux, activation of a pertussis toxin (PTX)-sensitive G-protein, inositol-trisphosphate (IP3) formation, intracellular Ca2+ release and PKC activity. Subliminal sustained membrane depolarization became efficient in inducing IP3 formation, release of intracellular Ca2+ and in blocking Ca2+ channels, when applied concomitantly with the mGlu7a receptor agonist, D,L-aminophosphonobutyrate (D,L-AP4). This synergistic effect of membrane depolarization and mGlu7 receptor activation provides a mechanism by which neuronal excitation could control action of the mGlu7 receptor in neurons.