Metabotropic glutamate receptors: From the workbench to the bedside

Abstract

Metabotropic glutamate (mGlu) receptors were discovered in the mid 1980s and originally described as glutamate receptors coupled to polyphosphoinositide hydrolysis. Almost 6500 articles have been published since then, and subtype-selective mGlu receptor ligands are now under clinical development for the treatment of a variety of disorders such as Fragile-X syndrome, schizophrenia, Parkinson’s disease and L-DOPA-induced dyskinesias, generalized anxiety disorder, chronic pain, and gastroesophageal reflux disorder. Prof. Erminio Costa was linked to the early times of the mGlu receptor history, when a few research groups challenged the general belief that glutamate could only activate ionotropic receptors and all metabolic responses to glutamate were secondary to calcium entry. This review moves from those nostalgic times to the most recent advances in the physiology and pharmacology of mGlu receptors, and highlights the role of individual mGlu receptor subtypes in the pathophysiology of human disorders. This article is part of a Special Issue entitled ‘Trends in Neuropharmacology: In Memory of Erminio Costa’.

Allosteric modulation of metabotropic glutamate receptors by chloride ions

“…The GPCRs activated by the neurotransmitter glutamate, also called metabotropic glutamate receptors (mGluRs), are key modulators of neurotransmission in the CNS (7,8). The mGluR family is composed of 8 members [metabotropic glutamate (mGlu) [1][2][3][4][5][6][7][8] and is divided into 3 groups.…”

“…The mGluR family is composed of 8 members [metabotropic glutamate (mGlu) [1][2][3][4][5][6][7][8] and is divided into 3 groups. Group I mGluRs (mGlu1 and 5) are postsynaptic receptors that positively modulate neuronal excitability.…”

Acid-sensing ion channel 1a is required for mGlu receptor dependent long-term depression in the hippocampus

“…The idea that protons can function as a neurotransmitter has existed for some time [35][36][37], however the precise role of ASICs in synaptic transmission and neuroplasticity remains still elusive [16,[37][38][39]. In fact, it has been suggested that ASIC1a may contribute to certain forms of synaptic plasticity in the hippocampus, although results are controversial [8,17,18].…”

Control of neuronal excitability by Group I metabotropic glutamate receptors

“…The development and characterization of selective agonists and antagonists for mGlu receptors has greatly facilitated the study of their role in physiological and pathological responses (Hovelsø et al 2012;Maksymetz et al 2017;Nicoletti et al 2011;Niswender and Conn 2010;Zou et al 2017). Metabotropic glutamate receptors have binding sites for two classes of ligands.…”