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+ (Ca(2+)circle) whereas CaR activity is potentiated by L-amino acids. We show that both mGluR1 and mGluR2 are activated by Ca, in the absence of glutamate in the extracellular media. This activation by Ca(2+)circle is antagonized by Mg(2+)circle. Unlike the CaR, in which the intracellular carboxyl tail has been reported to be involved in Ca(2+)circle-dependent activity, the carboxyl tail of mGluRs does not seem to play a role in mediating Ca(2+)circle 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 Ca(2+)circle as well as glutamate. Because the mGluR1 EC50 for Ca(2+)circle 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. (C) 2003 Wiley-Liss, Inc.