Subtype dependent NMDA receptor amino-terminal domain conformations and modulation by spermine [Membrane Biology]

March 31st, 2015 by Sirrieh, R. E., Maclean, D. M., Jayaraman, V.

The N-methyl-D-Aspartate (NMDA) subtype of the ionotropic glutamate receptors is the primary mediator of calcium permeable excitatory neurotransmission in the central nervous system. Subunit composition and binding of allosteric modulators to the amino-terminal domain determine the open probability of the channel. Using luminescence resonance energy transfer with functional receptors expressed in CHO cells, we show that the cleft of the amino-terminal domain of the GluN2B subunit, which has a lower channel open probability, is on average more closed than the GluN2A subunit, which has a higher open probability. Further, the GluN1 amino-terminal domain adopts a more open conformation when coassembled with GluN2A than with GluN2B. Binding of spermine, an allosteric potentiator, opens the amino-terminal domain cleft of both the GluN2B subunit and the adjacent GluN1 subunit. These studies provide direct structural evidence that the inherent conformations of the amino-terminal domains vary based on the subunit and match the reported open probabilities for the receptor.