Effects of Extracellular Calcium on the Modulation of Metabotropic Glutamate Receptor 1 Alpha (mGluR1α) by L-Quis, (S)-Mcpg, Cpccoet and Ro 67-4853

Abstract

Metabotropic glutamate receptor 1α (mGluR1α), known as a member of the family C GPCRs, couples to Gq and modulates consequent PLC activity, IP3 accumulation and intracellular Ca2+ release from ER lumen. mGluR1α is abundantly expressed in the central nervous system and has been shown to be responsible for the slow phase of the action potential in post-synaptic neurons, and to be involved in chronic neuronal degenerative diseases, like Parkinson's disease, Huntington's disease and Alzheimer's disease. We have predicted a potential Ca2+ binding site adjacent to the binding site previously reported for the endogenous agonist, glutamate, and receptor antagonists. In this study, we have applied single cell imaging and a radioactive binding assay to probe the effects of extracellular calcium in modulating various drugs modulating mGluR1α such as agonists, antagonists and allosteric modulators. We have shown that extracellular Ca2+ enhances the activation of the the receptor by its agonists and positive allosteric modulators by interacting with the Ca2+ binding site. In addition, extracellular Ca2+ differentially reduces the inhibition of the receptor by antagonists and negative allosteric modulators. Our studies open a new avenue for modulating drug effects and developing novel drugs against neurodegenerative diseases.