In this study we have investigated mechanisms underlying enhancement by group II metabotropic glutamate (mGlu) receptors of group I mGlu receptor-induced calcium mobilization. Inhibition of protein kinase A (PKA) caused an enhancement of mGlu5 receptor-mediated calcium mobilization and occluded the enhancement by group II mGlu receptors. A peptide (Ht31) that prevents interaction between A-kinase anchoring protein (AKAP) and PKA also enhanced mGlu5-mediated calcium mobilization. Enhancement of mGlu5 function, by inhibition of PKA or by activation of group II mGlu receptors, was prevented by the protein phosphatase 2B (PP2B) inhibitor cyclosporin A. Furthermore, the enhancement by activation of group II mGlu receptors was prevented by raising intracellular cAMP. These results suggest that the regulation by PKA and PP2B of phosphorylation of a substrate on mGlu5 and/or on group II mGlu receptors is intimately involved in the mechanisms underlying interaction between group II mGlu and mGlu5 receptors. Long-term depression (LTD) in perirhinal cortex requires group I, group II and NMDA receptor activation at resting membrane potentials but does not require group II mGlu receptor activation at depolarized potentials. We previously suggested that interaction between group I and group II mGlu receptors is required for induction of LTD at resting potentials. In support of this, we have demonstrated in perirhinal cortex slices that blocking mechanisms underlying mGlu receptor synergy (by raising intracellular cAMP or by inhibition of PP2B) selectively prevented LTD at resting membrane potentials. This study thus provides a potential explanation for the co-requirement in LTD of group I and group II mGlu receptor activation. Similar mechanisms of synergistic interaction may also be important in other physiological processes dependent on mGlu receptors.