Roles of subunit phosphorylation in regulating glutamate receptor function

Abstract

Protein phosphorylation is an important mechanism for regulating ionotropic glutamate receptors (iGluRs). Early studies have established that major iGluR subtypes, including α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and N-methyl-d-aspartate (NMDA) receptors, are subject to phosphorylation. Multiple serine, threonine, and tyrosine residues predominantly within the C-terminal regions of AMPA receptor and NMDA receptor subunits have been identified as sensitive phosphorylation sites. These distinct sites undergo either constitutive phosphorylation or activity-dependent phosphorylation induced by changing cellular and synaptic inputs. An increasing number of synapse-enriched protein kinases have been found to phosphorylate iGluRs The common kinases include protein kinase A, protein kinase C, Ca(2+)/calmodulin-dependent protein kinase II, Src/Fyn non-receptor tyrosine kinases, and cyclin dependent kinase-5. Regulated phosphorylation plays a well-documented role in modulating the biochemical, biophysical, and functional properties of the receptor. In the future, identifying the precise mechanisms how phosphorylation regulates iGluR activities and finding the link between iGluR phosphorylation and the pathogenesis of various brain diseases, including psychiatric and neurodegenerative diseases, chronic pain, stroke, Alzheimer's disease and substance addiction, will be hot topics and could contribute to the development of novel pharmacotherapies, by targeting the defined phosphorylation process, for suppressing iGluR-related disorders.

Keywords: AMPA; CaMKII; Cdk5; Excitatory amino acid; NMDA; PKA; PKC; Tyrosine kinase.

Figure 1. Phosphorylation sites in the CT regions of AMPA receptor and NMDA receptor subunits

Multiple serine, threonine, and tyrosine phosphorylation sites have been identified in the CT regions of AMPA receptor subunits (GluA1, GluA2, and GluA4) and NMDA receptor subunits (GluN1, GluN2A, and GluN2B). The GluN2A CT and GluN2B CT are particularly large, containing 627 and 644 amino acids (aa), respectively. Most phosphorylation sites in the GluN2A/B CT are located in the distal segments.