Abstract
Group I metabotropic glutamate (mGlu) receptors (mGlu1/5 subtypes) are G protein-coupled receptors and are broadly expressed in the mammalian brain. These receptors play key roles in the modulation of normal glutamatergic transmission and synaptic plasticity, and abnormal mGlu1/5 signaling is linked to the pathogenesis and symptomatology of various mental and neurological disorders. Group I mGlu receptors are noticeably regulated via a mechanism involving dynamic protein–protein interactions. Several synaptic protein kinases were recently found to directly bind to the intracellular domains of mGlu1/5 receptors and phosphorylate the receptors at distinct amino acid residues. A variety of scaffolding and adaptor proteins also interact with mGlu1/5. Constitutive or activity-dependent interactions between mGlu1/5 and their interacting partners modulate trafficking, anchoring, and expression of the receptors. The mGlu1/5-associated proteins also finetune the efficacy of mGlu1/5 postreceptor signaling and mGlu1/5-mediated synaptic plasticity. This review analyzes the data from recent studies and provides an update on the biochemical and physiological properties of a set of proteins or molecules that interact with and thus regulate mGlu1/5 receptors.
Highlights
L -Glutamate is a key neurotransmitter in the mammalian brain and is involved in the regulation of various neuronal and synaptic activities through activating two classes of receptors: ionotropic glutamate receptors and metabotropic glutamate receptors. iGlu receptors are ligand-gated ion channels and mediate fast excitatory synaptic transmission. Based on their ligand binding properties and sequence similarity, iGlu receptors are divided into four subtypes: α-amino-3-hydroxy5-methylisoxazole-4-propionic acid (AMPA) receptors, kainate receptors, N-methyl-D aspartate (NMDA) receptors, and delta receptors [1]. mGlu receptors represent a family of G protein-coupled receptors (GPCRs)
The long-form group I mGlu variants, i.e., mGlu1a, mGlu5a, and mGlu5b, are characterized by a unique long CT region, which provides a solid basis for protein–protein interactions and the interaction-dependent modulations
A panel of protein kinases are among mGlu1/5 interacting partners that were extensively investigated in recent years in heterologous expression systems and in neurons
Summary
L -Glutamate (glutamate) is a key neurotransmitter in the mammalian brain and is involved in the regulation of various neuronal and synaptic activities through activating two classes of receptors: ionotropic glutamate (iGlu) receptors and metabotropic glutamate (mGlu) receptors. iGlu receptors are ligand-gated ion channels and mediate fast excitatory synaptic transmission. Several categories of membrane-bound or cytoplasmic proteins access and bind to group I receptors [3,4] Among these binding proteins are protein kinases, such as mitogen-activated protein kinases (MAPKs), Src family kinases (SFKs), Ca2+ /calmodulin-dependent protein kinase II (CaMKII), and PKC [3,4,5,6]. These kinases are present within the PSD microdomain, bind to intracellular domains of mGlu1/5 receptors, especially the CT region, and phosphorylate specific residues on the receptors. This review summarizes the data primarily from the last five years of research and attempts to provide an update on this important topic
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