Modulation of Metabotropic Glutamate Receptors by Orthosteric, Allosteric, and Light-Operated Ligands

Glutamate is the major excitatory neurotransmitter of the mammalian central nervous system (CNS). Its actions are mediated by two broad classes of receptors: ligand-gated ion channels and G-protein-coupled receptors (GPCRs), named ionotropic and metabotropic glutamate receptors (mGluRs), respectively. The mGluR family consists of eight subtypes which are responsible for glutamate neuromodulatory actions throughout the CNS. These receptors are complex allosteric machines, offering multiple possibilities to regulate their activity. Their structure is composed of a seven-helix transmembrane domain, common to all GPCRs, and a large bilobate extracellular domain (ECD) where glutamate binds. Moreover, mGluRs are constitutive dimers crosslinked by a disulfide bridge. This chapter will provide an overview of mGluR structure, dynamics, and pharmacology, describing the different types of pharmacological tools that modulate mGluRs function, from orthosteric to allosteric molecules, including nanobodies, ions, and light-operated ligands.