Divalent cations modulate the activity of metabotropic glutamate receptors

Metabotropic glutamate receptors (mGluRs) and calcium receptors (CaR) are closely related G protein-coupled receptors (GPCRs). The similar structural and functional properties of mGluRs and CaRs include conserved amino acid residues involved in glutamate binding in mGluRs and Ca2+ binding in the CaR. Furthermore, recent findings have demonstrated that mGluRs can respond to high extracellular Ca2+ (Ca2+(o)) whereas CaR activity is potentiated by L-amino acids. We show that both mGluR1 and mGluR2 are activated by Ca2+(o) in the absence of glutamate in the extracellular media. This activation by Ca2+(o) is antagonized by Mg2+(o). Unlike the CaR, in which the intracellular carboxyl tail has been reported to be involved in Ca2+(o)-dependent activity, the carboxyl tail of mGluRs does not seem to play a role in mediating Ca2+(o) actions. On the other hand, we find that preservation of disulfide bonds in the N-terminal extracellular domain of mGluRs is essential for stimulation by Ca2+(o) as well as glutamate. Because the mGluR1 EC50 for Ca2+(o) is within the physiologic range of Ca2+ in the synaptic cleft, mGluR function is likely regulated by changes in divalent cations caused by synaptic activity under normal or pathologic conditions.