Glutamate receptors (GluRs), the major excitatory receptor in the brain, are characterized as ionotropic or metabotropic. Ionotropic GluRs are tetrameric ligand-gated cation channels that induce depolarization of the postsynaptic membrane following the presynaptic release of glutamate. Their actions underlie the cellular models of learning and memory, modulate the excitability of neuronal networks, and are required for synaptic maturation. Ionotropic GluRs can be pharmacologically classified according to their sensitivity to AMPA, Kainate, and NMDA. AMPA receptors (GluR1-4) evoke excitatory postsynaptic potentials and mediate fast (< 10 ms) synaptic transmission. In contrast, Kainate receptors (GluR5-6 and KA1/2) and NMDA receptors (NR1-3) mediate slower synaptic transmission (10 – 100 ms) exert effects on plasticity.
In addition, glutamate can modulate neuronal excitability and synaptic transmission through second messenger signaling pathways. Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors that function as constitutive dimers. There are eight mGluR subtypes that are differentially expressed in specific neuronal populations throughout the CNS. Metabotropic glutamate receptors are classified into three groups based on sequence homology, G protein-coupling, and ligand selectivity. In general, group I mGluRs (mGluR1 and 5) are expressed on postsynaptic membranes and function to increase neuronal excitability. In contrast, group II (mGluR2 and 3) and group III (mGluR4, 6, 7, and 8) mGluRs are expressed on presynaptic terminals or preterminal axons where they function to inhibit neurotransmitter release.