Metabotropic glutamate receptors and neurodegenerative diseases.

Glutamate is the most important excitatory neurotransmitter of the mammalian central nervous system (CNS), playing an important role in memory, synaptic plasticity and neuronal development. However, glutamate overstimulation is also implicated in neuronal cell death. There are two major types of glutamate receptors: ionotropic and metabotropic. Thus far, eight metabotropic glutamate receptors (mGluRs) subtypes have been characterized and are divided into three subgroups based on sequence homology and cell signaling activation. mGluRs activate a wide variety of cell signaling pathways by G protein-coupled pathways or via G protein-independent cell signaling activation. Moreover, these receptors exhibit widespread distribution in the CNS and are implicated in several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). This review aims to discuss the latest updates concerning mGluRs and their role in neurodegenerative diseases. mGluRs agonists and antagonists as well as positive and negative allosteric modulators have been tested in several animal models of neurodegenerative diseases. Furthermore, mGluR knockout mouse models have been crossed to mouse models of AD and HD, providing important data about mGluRs role in neurodegenerative disease progression. Thus, mGluRs constitute potential therapeutic targets for the development of therapies to treat neurodegenerative diseases.

Ribeiro FM ，Vieira LB ，Pires RG ，Olmo RP ，Ferguson SS ... -  《-》

Driving cellular plasticity and survival through the signal transduction pathways of metabotropic glutamate receptors.

Maiese K ，Chong ZZ ，Li F 《CURRENT NEUROVASCULAR RESEARCH》

Targeting mGluR group III for the treatment of neurodegenerative diseases.

Glutamate, an excitatory neurotransmitter, is essential for neuronal function, and it acts on ionotropic or metabotropic glutamate receptors (mGluRs). A disturbance in glutamatergic signaling is a hallmark of many neurodegenerative diseases. Developing disease-modifying treatments for neurodegenerative diseases targeting glutamate receptors is a promising avenue. The understudied group III mGluR 4, 6-8 are commonly found in the presynaptic membrane, and their activation inhibits glutamate release. Thus, targeted mGluRs therapies could aid in treating neurodegenerative diseases. This review describes group III mGluRs and their pharmacological ligands in the context of amyotrophic lateral sclerosis, Parkinson's, Alzheimer's, and Huntington's diseases. Attempts to evaluate the efficacy of these drugs in clinical trials are also discussed. Despite a growing list of group III mGluR-specific pharmacological ligands, research on the use of these drugs in neurodegenerative diseases is limited, except for Parkinson's disease. Future efforts should focus on delineating the contribution of group III mGluR to neurodegeneration and developing novel ligands with superior efficacy and a favorable side effect profile for the treatment of neurodegenerative diseases.

Rabeh N ，Hajjar B ，Maraka JO ，Sammanasunathan AF ，Khan M ，Alkhaaldi SMI ，Mansour S ，Almheiri RT ，Hamdan H ，Abd-Elrahman KS ... -  《-》

Supraspinal metabotropic glutamate receptors: a target for pain relief and beyond.

Glutamate is the main excitatory neurotransmitter in the central nervous system, controlling the majority of synapses. Apart from neurodegenerative diseases, growing evidence suggests that glutamate is involved in psychiatric and neurological disorders, including pain. Glutamate signaling is mediated via ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). So far, drugs acting via modulation of glutamatergic system are few in number, and all are associated with iGluRs and important side effects. The glutamatergic system may be finely modulated by mGluRs. Signaling via these receptors is slower and longer-lasting, and permits fine-tuning of glutamate transmission. There have been eight mGluRs cloned to date (mGluR1-mGluR8), and these are further divided into three groups on the basis of sequence homology, pharmacological profile, and second messenger signaling. The pattern of expression of mGluRs along the pain neuraxis makes them suitable substrates for the design of novel analgesics. This review will focus on the supraspinal mGluRs, whose pharmacological manipulation generates a variety of effects, which depend on the synaptic location, the cell type on which they are located, and the expression in particular pain modulation areas, such as the periaqueductal gray, which plays a major role in the descending modulation of pain, and the central nucleus of the amygdala, which is an important center for the processing of emotional information associated with pain. A particular emphasis will also be given to the novel selective mGluR subtype ligands, as well as positive and negative allosteric modulators, which have permitted discrimination of the individual roles of the different mGluR subtypes, and subtle modulation of central nervous system functioning and related disorders.

Palazzo E ，Marabese I ，de Novellis V ，Rossi F ，Maione S ... -  《-》

Glutamatergic Signaling in the Central Nervous System: Ionotropic and Metabotropic Receptors in Concert.

Glutamate serves as both the mammalian brain's primary excitatory neurotransmitter and as a key neuromodulator to control synapse and circuit function over a wide range of spatial and temporal scales. This functional diversity is decoded by two receptor families: ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). The challenges posed by the complexity and physiological importance of each of these subtypes has limited our appreciation and understanding of how these receptors work in concert. In this review, by comparing both receptor families with a focus on their crosstalk, we argue for a more holistic understanding of neural glutamate signaling.

Reiner A ，Levitz J 《-》