Molecular Biology and Ontogeny of Glutamate Receptors in the Mammalian Central Nervous System

Glutamate is the principal excitatory neurotransmitter in the mammalian central nervous system. After release from presynaptic terminals, glutamate binds to both ionotropic and metabotropic receptors to mediate fast, slow, and persistent effects on synaptic transmission and integrity. There are three types of ionotropic glutamate receptors. N-Methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA), and kainate receptors are principally activated by the agonist bearing its name and are permeable to cationic flux; hence, their activation results in membrane depolarization. All ionotropic glutamate receptors are believed to be composed of four distinct subunits, each of which is topologically arranged with three transmembrane-spanning and one pore-lining (hairpin loop) domain. In contrast, metabotropic glutamate receptors are G protein (guanine nucleotide-binding protein) -coupled receptors linked to second-messenger systems. Group I metabotropic glutamate receptors are linked to phospholipase C, which results in phosphoinositide hydrolysis and release of calcium from intracellular stores. Group II and group III metabotropic glutamate receptors are negatively linked to adenylate cyclase, which catalyzes the production of cyclic adenosine monophosphate. Each metabotropic glutamate receptor is composed of seven transmembrane-spanning domains, similar to other members of the superfamily of metabotropic receptors, which includes noradrenergic, muscarinic acetylcholinergic, dopaminergic, serotonergic (except type 3 receptors), and γ-aminobutyric acid (GABA) type B receptors. This review summarizes the relevant molecular biology and ontogeny of glutamate receptors in the central nervous system and highlights some of the roles that they can play during brain development and in certain disease states. (J Child Neurol 2004;19:343-360).