NMDA recep
tors are a family of glu
tama
te-ga
ted ion channels
tha
t regula
te various CNS func
tions such as?synap
tic plas
tici
ty and learning. However hypo- or hyper-ac
tiva
tion of NMDA recep
tors is cri
tically involved in many neurological and psychia
tric condi
tions such as pain, s
troke, epilepsy, neurodegenera
tion, schizophrenia, and depression. Thus, i
t is impor
tan
t to iden
tify mechanisms (such as by
targe
ted ubiqui
tina
tion)
tha
t regula
te
the levels of individual sub
types of NMDA recep
tors. In
this s
tudy, we used a series of
tagged, carboxy
terminal cons
truc
ts of GluN2D
to iden
tify associa
ting pro
teins from ra
t brain. Of seven differen
t GluN2D C-
terminal fragmen
ts used as bai
t, only
the cons
truc
t con
taining amino acids 983-1097 associa
ted wi
th an E3 ubiqui
tin ligase, Nedd4. A direc
t in
terac
tion be
tween GluN2D and Nedd4 was confirmed bo
th
in?vivo and
in?vitro. This associa
tion is media
ted by an in
terac
tion be
tween GluN2D's C-
terminal PPXY mo
tif and
the 2nd and 3rd WW domains of Nedd4. Of
the four GluN2 subuni
ts, Nedd4 direc
tly in
terac
ted wi
th GluN2D and also weakly wi
th GluN2A. Nedd4 coexpression wi
th GluN2D enhances GluN2D ubiqui
tina
tion and reduces GluN1/GluN2D NMDA recep
tor responses. These resul
ts iden
tify Nedd4 as a novel binding par
tner for GluN2D and sugges
t a mechanism for
the regula
tion of NMDA recep
tors
tha
t con
tain GluN2D subuni
ts
through ubiqui
tina
tion-dependen
t downregula
tion.
This article is part of the Special Issue entitled ¡®Glutamate Receptor-Dependent Synaptic Plasticity¡¯.