The N-terminal Domain Modulates α-Amino-3-hydroxy-5methyl-4-isoxazolepropionic acid ( AMPA) Receptor Desensitization

Background: The function of the AMPA receptor N-terminal domain (NTD) is unknown. Results: Deletion of the NTD leads to reduced desensitization and surface expression of GluA1-4 AMPA receptors. Conclusion: The NTD has a strong influence on the function and biosynthetic maturation of AMPA receptors. Significance: The NTD has the potential to mediate allosteric regulation of AMPA receptor signaling. AMPA receptors are tetrameric glutamate-gated ion channels that mediate fast synaptic neurotransmission in mammalian brain. Their subunits contain a two-lobed N-terminal domain (NTD) that comprises over 40% of the mature polypeptide. The NTD is not obligatory for the assembly of tetrameric receptors, and its functional role is still unclear. By analyzing full-length and NTD-deleted GluA1-4 AMPA receptors expressed in HEK 293 cells, we found that the removal of the NTD leads to a significant reduction in receptor transport to the plasma membrane, a higher steady state-to-peak current ratio of glutamate responses, and strongly increased sensitivity to glutamate toxicity in cell culture. Further analyses showed that NTD-deleted receptors display both a slower onset of desensitization and a faster recovery from desensitization of agonist responses. Our results indicate that the NTD promotes the biosynthetic maturation of AMPA receptors and, for membrane-expressed channels, enhances the stability of the desensitized state. Moreover, these findings suggest that interactions of the NTD with extracellular/synaptic ligands may be able to fine-tune AMPA receptor-mediated responses, in analogy with the allosteric regulatory role demonstrated for the NTD of NMDA receptors.