Modulating Drug Effects of Metabotropic Glutamate Receptor 1 Alpha (mGluR1α) by Extracellular Ca2+

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+ extrusion from ER lumen. The mGluR1α is abundantly expressed in central nervous system and has been shown to be responsive to the slow phase of the action potential in post-synapses, 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 to reported endogenous agonist glutamate and antagonists. In this study, we have applied single cell imaging, IP1 binding, and radioactive assay to probe the effect of extracellular calcium in modulating various types of the drugs of modulating mGluR1a such as agonists, antagonists and allosteric modulators. We have shown that extracellular Ca2+ enhances the agonist's activation of intracellular calcium responses of mGluR1α by increasing the drug binding to the receptor. In addition, extracellular Ca2+ also differentially modulates the inhibition of the receptor by antagonists and allosteric modulators. Our studies open a new avenue for modulating drug effects and developing novel drugs against neurodegenerative diseases.