Metabotropic glutamate receptor subtype 5: molecular pharmacology, allosteric modulation and stimulus bias

Abstract

The metabotropic glutamate receptor subtype 5 (mGlu5 ) is a family C GPCR that has been implicated in various neuronal processes and, consequently, in several CNS disorders. Over the past few decades, GPCR-based drug discovery, including that for mGlu5 receptors, has turned considerable attention to targeting allosteric binding sites. Modulation of endogenous agonists by allosteric ligands offers the advantages of spatial and temporal fine-tuning of receptor activity, increased selectivity and reduced adverse effects with the potential to elicit improved clinical outcomes. Further, with greater appreciation of the multifaceted nature of the transduction of mGlu5 receptor signalling, it is increasingly apparent that drug discovery must take into consideration unique receptor conformations and the potential for stimulus-bias. This novel paradigm proposes that different ligands may differentially modulate distinct signalling pathways arising from the same receptor. We review our current understanding of the complexities of mGlu5 receptor signalling and regulation, and how these relate to allosteric ligands. Ultimately, a deeper appreciation of these relationships will provide the foundation for targeted drug design of compounds with increased selectivity, not only for the desired receptor but also for the desired signalling outcome from the receptor. Linked Articles This article is part of a themed section on Molecular Pharmacology of G Protein-Coupled Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.20/issuetoc.

Biased allosteric agonism and modulation of metabotropic glutamate receptor 5: Implications for optimizing preclinical neuroscience drug discovery

“…Therefore it was unexpected that ligands that were agonists for IP 1 had lower potency or efficacy in iCa 2+ assays. However, it is also well-known that mGlu 5 couples to various calcium ion channels (Sengmany and Gregory, 2015). Hence, iCa 2+ mobilization detected upon receptor activation may be the combination of both extracellular calcium entering the cell via ion channels, and the calcium released from internal stores.…”

“…In particular, while the receptor is predominantly coupled to G q and subsequent changes in intracellular calcium (iCa 2+ ) mobilization, mGlu 5 couples to iCa 2+ -independent signaling pathways, such as extracellular signal-regulated kinases (ERK) 1 and 2 phosphorylation, cAMP, mTOR/PI3K, and can interact with, and modulate the activity of, other GPCRs and ion channels (Sengmany and Gregory, 2015). It is conceivable therefore that mGlu 5 activation by chemically diverse ligands may engender unique receptor conformations, such that the receptor favors distinct subsets of physiological responses.…”

Automated cGMP‐compliant radiosynthesis of [18F]‐(E)‐PSS232 for brain PET imaging of metabotropic glutamate receptor subtype 5

“…Among the identified mGluRs, subtype 5 (mGlu 5 ) is abundant in brain regions such as the striatum, hippocampus, and cortex. mGlu 5 plays a crucial role in synaptic transmission and neuronal excitability by regulating physiological glutamate levels . Dysfunction of mGlu 5 is often associated with neuropsychiatric disorders, including schizophrenia, anxiety, depression, addiction, Parkinson's disease, and Fragile X syndrome .…”

Molecular pharmacology of G protein‐coupled receptors

“…Biased signalling is also a feature of the paper by Kathy Sengmany and Karen Gregory (Sengmany and Gregory, ) that describes the molecular pharmacology, allosteric modulation and stimulus bias at the metabotropic glutamate receptor subtype 5 (mGlu 5 ). The receptor is G q/11 coupled to PLC and is activated by a unique fly trap domain with lobes that close around glutamate during receptor activation.…”