GRIN1 variants associated with neurodevelopmental disorders reveal channel gating pathomechanisms.

Our data demonstrate that the GluN1(I481V) variant is inhibited by the open pore blockers, ketamine and memantine with reduced potency but otherwise has little effect on receptor function. By contrast, the other two variants exhibit gain-of-function molecular phenotypes. Glycine sensitivity was enhanced in receptors containing the GluN1(A666S) variant and the potency of pore block by memantine and ketamine was reduced, whereas that for MK-801 was increased. The most pronounced functional deficits, however, were found in receptors containing the GluN1(Y668H) variant. GluN1(Y668H)/2A receptors showed impaired surface expression, were more sensitive to glycine and glutamate by an order of magnitude and exhibited impaired block by extracellular magnesium ions, memantine, ketamine and MK-801. These variant receptors were also activated by either glutamate or glycine alone. Single receptor recordings revealed that this receptor variant opened to several conductance levels and activated more frequently than wild-type GluN1/2A receptors. This article is protected by copyright. All rights reserved.