Abstract
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 Ca2+ 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 Ca2+ in regulation of mGluRs, summarize the recent developments in probing Ca2+ binding and its co-regulation of the receptor based on structural and biochemical analysis, and discuss the molecular basis for Ca2+ to regulate various classes of drug action as well as its importance as an allosteric modulator in mGluRs.
Highlights
Ca2+, as a first and second messenger, regulates numerous cellular processes through temporal and spatial changes in its concentration and associated changes in the activity of Ca2+-receptor/binding proteins
C GPCR from humans is comprised of eight metabotropic glutamate receptors, two heterodimeric-aminobutyric acid B (GABAB) receptors, one calcium-sensing receptor (CaSR), three taste (T1R) receptors, one L-amino acid receptor (GPRC6A), and five orphan receptors
We firstly found that our predicted Ca2+-binding site is adjacent to the orthosteric agonist and antagonist interaction sites and exhibits a good dynamic correlated motion with these sites as assessed by molecular dynamics (MD) simulations
Summary
Ca2+, as a first and second messenger, regulates numerous cellular processes through temporal and spatial changes in its concentration and associated changes in the activity of Ca2+-receptor/binding proteins. Applying the mGluR antagonist (R,S)-α-methyl-4-carboxyphenyl-glycine (MCPG) dramatically decreased this [Ca2+]i, while blocking the receptor-operated and P-type Ca2+ channels by antagonist SKF-96365 and ω-agatoxin IVA did not significantly affect the [Ca2+]i responses to extracellular Ca2+ [54] This suggests that the increase of [Ca2+]i is not likely to be a result of Ca2+ influx through Ca2+ channels. Cytosolic Ca2+ increases upon extracellular Ca2+ activating mGluRs via release of ER Ca2+ due to the production of IP3 Such increases of [Ca2+]i in turn alter mGluR activity due to changes in the receptor expression on cell surface in several aspects (Figure 1). Mutants of mGluR1 lacking of caveolin binding motif were demonstrated to attenuate mGluR1 coupled ERK-MAPK signaling pathway [63]
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