Ionotropic Glutamate Receptors

Abstract

On this planet, the mammalian brain is probably the most complex cellular network. In this system, glutamate is the dominant neurotransmitter, and it mediates the fast communication between the units of the network. Glutamate’s main sites of action are the ionotropic glutamate receptors (iGluRs) and G-protein-coupled metabotropic glutamate receptors (mGluRs) (Fig. 1). iGluRs are a group of receptors that are related in their amino acid sequences and belong to the huge super family of ion channels containing a P-loop as ion-pore-forming segment. These P-loop channels consist of several subunits. In the case of iGluRs, this subunit assembly is tetrameric. Each iGluR subunit has an extracellular amino-terminal domain, three membrane-spanning helices, and the P-loop between helices M1 and M3. On each subunit, the ligand binds to an extracellular glutamate-binding site formed by the two extracellular domains of the subunit. Glutamate binding leads to a bending of helix M1 and M2, followed by an opening of the channel. The P-loops of the four subunits form the channel pore and determine whether the ion channel is selective for monovalent or divalent ions (or both). The carboxy-terminus lies within the cell and can interact with intracellular signaling and scaffolding proteins. Most iGluRs are associated with auxiliary proteins. The auxiliary proteins can be involved in surface delivery and trafficking of the iGluR, but they can also modulate iGluR channel properties. Some of these auxiliary proteins are obligatory for iGluRs, while others are facultative modifiers.

The iGluR family consists of four subgroups: AMPA, NMDA, kainate, and orphan receptors (Fig. 1), distinguished by their pharmacological profile. Each subgroup has a particular function. Kainate and orphan receptors have not yet been characterized in detail: The kainate receptors form fast channels, but no ion channel function has so far been found for the orphan receptors. The AMPA receptors are strongly expressed everywhere in the brain. They are directly responsible for the fast signal transmission at synapses, which represent the communication points between the individual units (nerve cells, also termed neurons). A similar strong expression has been found for the NMDA receptors. However, the NMDA receptors do not directly participate in fast synaptic transmission; instead, they are the most fundamental modulators of the strength of the synaptic AMPA receptor currents. Most importantly, the NMDA receptor-induced modulation of the AMPA receptor currents at the junctions between neurons is a basis for network formation during development. Moreover, in the mature brain, the NMDA receptors keep synapses modifiable and thus permit a continuous incorporation or removal of new information into and from the network; in other words, the NMDA receptors are necessary for the formation and the extinction of memory. This simple picture of iGluR functions is, however, likely to be substantially modified in the future, in view of the great complexity of the iGluR system described below.