Cross-subunit interactions that stabilize open states mediate gating in NMDA receptors

NMDA receptors are excitatory channels with critical functions in the physiology of central synapses. Their activation reaction proceeds as a series of kinetically distinguishable, reversible steps, whose structural bases are currently under investigation. Very likely, the earliest steps include glutamate binding to glycine-bound receptors and subsequent constriction of the ligand-binding domain. Later, three short linkers transduce this movement to open the gate by mechanical pulling on transmembrane helices. Here, we used molecular and kinetic simulations and double-mutant cycle analyses to show that a direct chemical interaction between GluN1-I642 (on M3 helix) and GluN2A-L550 (on L1-M1 linker) stabilizes receptors after they have opened and thus represents one of the structural changes that occur late in the activation reaction. This native interaction extends the current decay, and its absence causes deficits in charge transfer by GluN1-I642L, a pathogenic human variant.

Automated summary

NMDA receptors are excitatory channels crucial for central synapse physiology. The activation process involves a series of kinetically distinguishable, reversible steps, starting with glutamate binding and ligand-binding domain constriction, followed by transducing movement through linkers to open the gate. This study reveals a direct chemical interaction between GluN1-I642 and GluN2A-L550 as a structural change late in the activation reaction, stabilizing the receptors after opening.