Glutamate receptors fall into two broad categories: IONOTROPIC and METABOTROPIC. Activation of ionotropic receptors leads to ION CHANNEL opening; activation of metabotropic glutamate receptors activates cell-signalling pathways (for example PROTEIN KINASE and PHOSPHOLIPASE). lonotropic glutamate receptors can be subdivided into two types—NMDA and non-NMDA receptors—with non-NMDA receptors further subdivided into AMPA and kainate receptors (receptors are all named after their definitive AGONIST). Any SYNAPSE that uses excitatory amino acid transmission may have a combination of ionotropic and metabotropic receptor-types available, and these may act synergistically.
Molecular cloning studies have since identified a number of different subunits which can combine to form a variety of subtypes of ionotropic or metabotropic glutamate receptor channels, and IN SITU HYBRIDIZATION studies have demonstrated considerable regional variability in the expression of the constituent subunit MESSENGER RNA throughout the brain. NMDA subunits include at least seven alternatively spliced variants of NR1 (or, more cumbersomely, NMDAR1), in addition to four NR2 subunits, NR2A to NR2D; to form a functional NMDA receptor, one of the consituent subunits must be NR1. AMPA receptors are the principal mediators of fast excitatory transmission (see FAST NEUROTRANSMISSION) and can also be activated by kainic acid. They are constructed from any homomeric or heteromeric combination of two subunits GluR1 to GluR4. In addition, there are at least two types of kainate receptors, which are not activated by AMPA. These are likely to be formed from HIGH AFFINITY kainate subunits such as KA1 and KA2, although these subunits themselves do not appear to form functional homomeric chan-nels. LOW-AFFINITY kainate subunits GluR5 to GluR7 share approximately 40% sequence identity with GluR1 to GluR4. There are at least 8 subtypes of metabotropic glutamate receptor, classified in subgroups according to sequence homology and on their pharmacology and transduction mechanisms when expressed in cell lines. For instance, Group 1 (mGluR1 and mGluR5) are coupled to phospholipase C.
