N-terminal Domain Modulates {alpha}-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Desensitization [Membrane Biology]
March 20th, 2014 by Moykkynen, T., Coleman, S. K., Semenov, A., Keinanen, K.
AMPA receptors are tetrameric glutamate-gated ion channels, which mediate fast synaptic neurotransmission in mammalian brain. Their subunits contain a two-lobed N-terminal domain (NTD) which 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 analysing full-length and NTD-deleted GluA1-4 AMPA receptors expressed in HEK 293 cells, we found that removal of NTD leads to significant reduction in receptor transport to the plasma membrane, higher steady state-to-peak current ratio of glutamate responses, and strongly increased sensitivity to glutamate toxicity in cell culture. Further analyses showed that all NTD-deleted receptors display both a slower onset of desensitization and a faster recovery from desensitization of agonist responses. Our results indicate that NTD promotes the biosynthetic maturation of AMPA receptors, and for membrane expressed channels, enhances the stability of the desensitized state. Moreover, the present findings suggest that interactions of 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