Metabotropic glutamate receptors in the trafficking of ionotropic glutamate and GABA(A) receptors at central synapses

Abstract

The trafficking of ionotropic glutamate (AMPA, NMDA and kainate) and GABA(A) receptors in and out of, or laterally along, the postsynaptic membrane has recently emerged as an important mechanism in the regulation of synaptic function, both under physiological and pathological conditions, such as information processing, learning and memory formation, neuronal development, and neurodegenerative diseases. Non-ionotropic glutamate receptors, primarily group I metabotropic glutamate receptors (mGluRs), co-exist with the postsynaptic ionotropic glutamate and GABA(A) receptors. The ability of mGluRs to regulate postsynaptic phosphorylation and Ca(2+) concentration, as well as their interactions with postsynaptic scaffolding/signaling proteins, makes them well suited to influence the trafficking of ionotropic glutamate and GABA(A) receptors. Recent studies have provided insights into how mGluRs may impose such an influence at central synapses, and thus how they may affect synaptic signaling and the maintenance of long-term synaptic plasticity. In this review we will discuss some of the recent progress in this area: i) long-term synaptic plasticity and the involvement of mGluRs; ii) ionotropic glutamate receptor trafficking and long-term synaptic plasticity; iii) the involvement of postsynaptic group I mGluRs in regulating ionotropic glutamate receptor trafficking; iv) involvement of postsynaptic group I mGluRs in regulating GABA(A) receptor trafficking; v) and the trafficking of postsynaptic group I mGluRs themselves.

Keywords: GABAA receptor; Metabotropic; endocytosis; glutamate receptor; hippocampus; ionotropic; receptor trafficking; synaptic plasticity.

Fig. (1)

Schematic structure and function of a hippocampal CA1 glutamatergic synapse. Postsynaptic AMPARs, NMDARs and kainate receptors are depicted as tetrameric complexes. AMPARs are linked to scaffolding proteins GRIP/ABP. NMDARs are associated with scaffolding and signaling proteins such as PSD-95, CaMKII, nNOS and GKAP. Kainate receptors are depicted alone for simplification. The mGluRs are illustrated as proteins with seven transmembrane segments. They are linked to a scaffolding protein Homer which in turn can mediate an interaction between mGluRs and NMDARs via Shank protein as well as mediate an interaction between mGluRs and intracellular Ca²⁺ stores via rP₃Rs. Cell adhesion molecules such as cadherins and neurexin/neuroligin link the presynaptic and postsynaptic membranes. Glutamate released from presynaptic vesicles by exocytosis mainly binds to postsynaptic AMPARs, NMDARs or kamate receptors which open channels, allowing various ions to pass. A rise in Ca²⁺ in the postsynaptic terminal can trigger intracellular signaling cascades which can alter the efficacy of synaptic transmission. The ion passage through the receptor channels results in synaptic currents and potentials which can be detected and recorded using electrophysiology techniques. Meanwhile, the released glutamate binds also to postsynaptic and presynaptic metabotropic glutamate receptors which results in changes in the protein kinase C (PKC) activity, Ca²⁺ release from intracellular stores or cAMP levels. A representative intracellular pool of AMPARs is also shown.