Abstract
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.
Highlights
The function of the AMPA receptor N-terminal domain (NTD) is unknown
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
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
Summary
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. 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. 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 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. The extracellular part of the receptor subunits is composed of two bilobed domains: the N-terminal domain (NTD) of ϳ400 amino acid residues and the ligand-binding domain (LBD), consisting of two separate, 120- to 150-residue segments, one situated between the NTD and the first transmembrane segment (M1) and the other following the second (M2). These findings indicate that the NTD imposes significant constraints on the conformational transitions of the LBD-ion channel core and underscore the role of the NTD in the biosynthetic maturation of AMPA receptors
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