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L-glutamate (Glu) is the main excitatory neurotransmitter in the Central Nervous System (CNS). The glutamate receptors (GluRs) are distributed in all CNS regions and they have been classified in two big families. The first big family is formed by the ionotropic glutamate receptors (iGluRs) or ligand-gated ion channels, which allow selective crossing of ions through selective ion channels permeable to Ca2+
. Depending of the electrophysiological and pharmacological properties of these receptors, they are classified in three families: the α-amino-3-hydroxi-5-methyl-4-isoxazol-propionic acid (AMPA) receptors, the kainate receptors (KA) and the N-methyl-D-aspartate (NMDA) receptors.
The general structure of iGluRs, consists of an extracellular amino terminal domain (NTD), two ligand-binding domains (S1 and S2), three trans-membrane segments (TM1, TM2 and TM3), a re-entrant pore loop and an intracellular carboxyl terminal domain (CTD). They are generally assembled into a tetrameric structure, formed by hetero-oligomeric integral protein subunits, which are encoded by different genes. The AMPA receptors family includes GluR-1, GluR-2, GluR-3 and GluR-4; the kainate receptors family comprises GluR-5, GluR-6, GluR-7, K1 and K2; and the NMDA receptors family is conformed by NR1, NR2 (NR2A-D) and NR3 (NR3A and 3B). In addition, alternative splicing of the primary transcripts increases the diversity of ionotropic receptor variants.
The second great family is composed by the metabotropic glutamate receptors (mGluRs), which are associated to G-proteins that work through intracellular signaling generated by second messengers (inositol 3-phosphate, diacylglycerol and cAMP). As a general characteristic of their structure, the mGluRs have a large extracellular NTD, seven transmembrane passages connected by intracellular and extracellular loops, and an intracellular CTD.
The mGluRs are divided in three groups: class I receptors include mGluR1 and mGluR5; class II receptors include mGluR2 and mGluR3; and class III receptors include mGluR4, mGluR6, mGluR7 and mGluR8. Generally, class I receptors are coupled to a Gq associated to phosphoinositides hydrolysis and function as postsynaptic receptors with an increased neuronal excitability. Class II and III receptors are coupled to Gi/Go, and are associated with adenylyl cyclase inhibition and function as pre-synaptic receptors diminishing neurotransmitter release. As in the case of iGluRs, there are many isoforms for mGluRs generated by alternative splicing of the pre-mRNA.
The physiological relevance for studying GluRs is due to the key role they play in various neurodegenerative diseases, such as Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, stroke, epilepsy, HIV dementia, Creutzfeld-Jacob's disease and hypoglycemia. They are also involved in psychiatric disorders like schizophrenia, depression, anxiety disorder and post-traumatic stress disease. Moreover, the GluRs are involved in all the related steps of CNS development and neuronal differentiation.
The great variability of responses to Glu is due in part to extracellular Glu concentration, as well as to the diversity of GluRs. It has been observed that differential expression of GluRs subunits is related to the stage of development and to the region of CNS. Thus, the pattern of differential expression of GluRs in a temporal and spatial manner is fundamental to understand the role of Glu in the CNS development.
During neurogenesis, the early developing brain contains high levels of extracellular Glu. The activation of different GluRs, activates in turn intracellular second messenger signaling pathways, modifying the intracellular calcium concentration [Ca2+]i, which triggers transcriptional activation of cell cycle regulatory genes that promote cellular growth, regeneration, differentiation and neuronal survival.
Furthermore, GluRs can stimulate growth of the pre-synaptic dendritic tree and harboring of post-synaptic dendrites, as well as to promote synaptic consolidation and maintenance. Other important mechanisms to generate mature neural networks are synaptic elimination, which diminishes the established neuronal contacts during synaptic refinement, and silencing of GluRs activity, which favors synaptic elimination during neuronal network formation. In addition, GluRs play an important role in the formation of inhibitory synapses during CNS development.
GluR activation promotes dendritic growth through the generation of intracellular second messengers. However, biphasic changes of [Ca2+
]i, in response to GluR activation, are related to the inhibitory and stimulatory dendritic growth phases. Therefore, a transitory increase of [Ca2+
]i is related to a calmodulin-dependent dendritic growth, while a sustain rise of intracellular calcium is related to a calpain-dependent dendritic retraction resulting in dendritic microtubule polymer reduction. Another mechanism for dendritic growth is mediated through extracellular calcium influx, which triggers a cascade of intracelullar signaling pathways, such as phosphorylation of Tiam1, Ras/Rac activation and recruiting protein kinases, phosphoinositide-dependent kinase and Akt, which are involved in the protein synthesis necessary for dendritic development and neuronal plasticity.
It has been shown that excessive GluR activation can alter neuronal migration. Superficial cortical neurons release Glu producing a concentration gradient, which in turn promotes neuronal migration to the cortical plate, changing the cytoskeleton dynamics. The neuronal migration rate depends on increased intracellular calcium through GluRs. The GluRs can inhibit migration due to cytoskeleton depolymerization, or due to mechanisms influencing the direction of the migration of phillopodias.
Although the NMDA receptors are the most studied in the development of CNS and during neuronal differentiation, in this review we also analyze the importance of the great variety of iGluRs and mGluRs during the development of the brain. We review the establishment and maintenance of synapses, cellular growth and differentiation through symmetric and asymmetric division, as well as neuronal survival, dendritic growth, synapsis elimination, receptor activity silencing and neuronal migration. All of the above processes play key steps in the establishment and development of mature neuronal networks, which are fundamental to consolidate the formation of all regions of the CNS from embryogenesis to adult life.
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