The glutamate story

Abstract

Glutamatergic synaptic transmission in the mammalian central nervous system was slowly established over a period of some 20 years, dating from the 1950s. Realisation that glutamate and like amino acids (collectively known as excitatory amino acids (EAA)) mediated their excitatory actions via multiple receptors preceded establishment of these receptors as synaptic transmitter receptors. EAA receptors were initially classified as N-methyl-D-aspartate (NMDA) and non-NMDA receptors, the latter subdivided into quisqualate (later AMPA) and kainate receptors after agonists that appeared to activate these receptors preferentially, and by their sensitivity to a range of differentially acting antagonists developed progressively during the 1970s. NMDA receptors were definitively shown to be synaptic receptors on spinal neurones by the sensitivity of certain excitatory pathways in the spinal cord to a range of specific NMDA receptor antagonists. Importantly, specific NMDA receptor antagonists appeared to be less effective at synapses in higher centres. In contrast, antagonists that also blocked non-NMDA as well as NMDA receptors were almost universally effective at blocking synaptic excitation within the brain and spinal cord, establishing both the existence and ubiquity of non-NMDA synaptic receptor systems throughout the CNS. In the early 1980s, NMDA receptors were shown to be involved in several central synaptic pathways, acting in concert with non-NMDA receptors under conditions where a protracted excitatory postsynaptic potential was effected in response to intense stimulation of presynaptic fibres. Such activation of NMDA receptors together with non-NMDA receptors led to the phenomenon of long-term potentiation (LTP), associated with lasting changes in synaptic efficacy (synaptic plasticity) and considered to be an important process in memory and learning. During the 1980s, it was shown that certain glutamate receptors in the brain mediated biochemical changes that were not susceptible to NMDA or non-NMDA receptor antagonists. This dichotomy was resolved in the early 1990s by the techniques of molecular biology, which identified two families of glutamate-binding receptor proteins (ionotropic (iGlu) and metabotropic (mGlu) receptors). Development of antagonists binding to specific protein subunits is currently enabling precise identification of discrete iGlu or mGlu receptor subtypes that participate in a range of central synaptic processes, including synaptic plasticity.

Figure 1

A range of key ligands for glutamate receptors indicating the extensive variation of the simple glutamate structure that has led to selective agonists and antagonists for specific receptor subtypes (see Table 1) (Stereochemical nomenclature: In the interests of readability we have not always stated the enantiomer of glutamate applying to each mention of the amino acid. Where no enantiomer is stated, the L form is assumed. The modern terms R and S are used for more recently prepared synthetic compounds, although D and L are retained for others, for example, N-methyl-D-aspartate (NMDA) and L-2-amino-4-phosphonobutyrate (LAP4)).

Figure 2

‘Three-point receptor' (Curtis & Watkins, 1960).

Figure 3

Crystal structure of L-glutamate bound to the S1S2 construct of GluR2. Note the α-carboxyl group of glutamate forms a salt bridge with Arg485 and a hydrogen bond with Thr480 while the ω-carboxyl group forms hydrogen bonds with Ser654 and Thr655. The α-amino group of glutamate forms a salt bridge with Glu705 and hydrogen bonds with Thr480 and Pro478.

Scheme 1

Classification of glutamate receptors.