Molecular Basis for Modulation of Metabotropic Glutamate Receptors and Their Drug Actions by Extracellular Ca(2+)

Metabotropic glutamate receptors (mGluRs) associated with the slow phase of the glutamatergic signaling pathway in neurons of the central nervous system have gained importance as drug targets for chronic neurodegenerative diseases. While extracellular Ca(2+) was reported to exhibit direct activation and modulation via an allosteric site, the identification of those binding sites was challenged by weak binding. Herein, we review the discovery of extracellular Ca(2+) in regulation of mGluRs, summarize the recent developments in probing Ca(2+) binding and its co-regulation of the receptor based on structural and biochemical analysis, and discuss the molecular basis for Ca(2+) to regulate various classes of drug action as well as its importance as an allosteric modulator in mGluRs.