Glutamate Receptor Signaling


Pathway Description

Glutamate is the most abundant excitatory neurotransmitter in the mammalian nervous system. It is stored in presynaptic vesicles and is released by calcium-dependent vesicular release. There are two kinds of glutamate receptors- the ionotropic receptors (GRI, related to ionic channels) or metabotropic receptors (GRM, related to metabolic formation of second messengers). Glutamate is removed from the synaptic cleft by reuptake into the presynaptic terminal or by uptake into glial cells, where it is converted to glutamine. The reuptake process is achieved by glutamate transporters; solute carrier family 1 (SLC1A).The level of glutamate available for neurosecretion in the presynaptic vesicles is determined by transport into the presynaptic vesicle. Glutamate enters the presynaptic vesicle by means of a specialized transporter, solute carrier family 17 (SLC17A).Glutamine that is obtained from glial cells has no neurotransmitter activity, and is converted back to glutamate by glutaminase (GLS) in the presynaptic neurons (glutamate-glutamine cycle).

The ionotropic glutamate receptors are ligand gated ion channels that have different affinities for agonists. Based on this, they are classified as N-methyl-D-aspartic acid (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainite or delta receptors (GRIN, GRIA, GRIK and GRID respectively). These ion channels conduct cations like Na+ and Ca2+ into the cell. The activation of the ligand gated cationic channels by glutamate results in Na+ mediated depolarization and development of excitatory post synaptic potential (EPSP)in the post synaptic membranes. The influx of Ca2+ on the other hand can result in the activation of Ca2+ dependent enzymes and secondary messengers, which in turn can lead to long term post synaptic modification. The function of ionotropic glutamate receptors can be enhanced by adapter proteins. Glutamate receptor interacting protein (GRIP) serves as an adapter protein that links AMPA receptors to other proteins and may be critical for the clustering of AMPA receptors at excitatory synapses in the brain. A similar adapter protein PSD 95 plays a role in clustering NMDA receptors.

The metabotropic glutamate receptors (GRM) are both functionally different from the family of the ionotropic receptors. The GRM is coupled to a G protein(s) and evokes a variety of effects by mediating intracellular signal transduction. Seven subtypes of GRM are known to exist and are classified on the basis of their association with a secondary messenger. GRM1 and GRM5 are associated with inositol tri phosphate (IP3) and changes in Ca2+ concentrations. GRM2, GRM3, GRM6 and GRM8 are associated with the inhibition of cAMP production. GRM7 can be associated with both IP3 as well as cAMP. GRM7 is involved in the inhibition of glutamate release from the presynaptic vesicles.

This pathway highlights the different kinds of glutamate receptors and their signaling.