Divalent cations modulate the activity of metabotropic glutamate receptors

J Neurosci Res. 2004 Feb 15;75(4):472-9. doi: 10.1002/jnr.10853.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Calcium / chemistry*
  • Cations, Divalent / chemistry
  • Cell Line
  • Dose-Response Relationship, Drug
  • Humans
  • Magnesium / chemistry*
  • Receptors, Metabotropic Glutamate / chemistry
  • Receptors, Metabotropic Glutamate / metabolism*
  • Zinc / chemistry*


  • Cations, Divalent
  • Receptors, Metabotropic Glutamate
  • Magnesium
  • Zinc
  • Calcium