Download The postsynaptic NMDA-receptor–PSD-95

CELL SCIENCE AT A GLANCE
The postsynaptic
NMDA-receptor–PSD-95
signaling complex in
excitatory synapses of
the brain
Morgan Sheng
MGH and Harvard Medical School, Howard Hughes
Medical Institute (Wellman 423), Massachusetts
General Hospital, 50 Blossom Street, Boston, MA
02114, USA
Excitatory synapses of the brain use as
neurotransmitter the amino acid
glutamate, which is released in packets
from the presynaptic terminal. The
postsynaptic membrane is specialized
for the reception of glutamate signals
and the transduction of these signals into
the postsynaptic cell. Containing a high
concentration of glutamate receptors and
associated cytoskeletal and signaling
proteins, the postsynaptic specialization
is visible by electron microscopy as a
thickening (~30 nm thick) of the
postsynaptic membrane known as the
Ca2+
1251
postsynaptic density (PSD). The NMDA
subtype
of
glutamate
receptor
(NMDAR) is an abundant constituent of
the PSD and functions as a glutamategated calcium-permeable ion channel.
NMDARs are anchored in the PSD by
interactions between the cytoplasmic Cterminal tails of their NR2 subunits and
the PDZ domains (orange) of PSD-95,
an abundant PSD protein that forms a
two-dimensional lattice immediately
under the postsynaptic membrane. The
PDZ domains of PSD-95 also bind to
other postsynaptic membrane proteins,
including potassium channels (K+ Ch),
tyrosine kinases (ErbB4) and cell
adhesion molecules (neuroligin). Having
multiple domains that bind to a variety
of cytoplasmic proteins, PSD-95
functions as a scaffold to assemble a
specific set of signaling proteins around
the NMDAR. These proteins, such as
neuronal nitric oxide synthase (nNOS),
SynGAP [a GTPase-activating protein
(GAP) for Ras] and SPAR (a GAP for
Rap), may participate in downstream
signaling by NMDARs. PSD-95, in turn,
bB
B4
interacts with GKAP and Shank, two
scaffold proteins lying in the deep part
of the PSD. Shank binds to Homer,
which interacts directly with the
cytoplasmic tail of the metabotropic
glutamate receptor (mGluR), a Gprotein-coupled glutamate receptor.
Homer forms multimers and additionally
binds to the inositol 1,4,5-trisphosphate
receptor [Ins(1,4,5)P3R] found in
smooth endoplasmic reticulum (SER),
thereby linking cell surface mGluRs to a
downstream effector [Ins(1,4,5)P3R] in
intracellular calcium stores. Thus an
extensive network of protein-protein
interactions within the PSD links
together different classes of postsynaptic
glutamate receptor and couples them to
specific intracellular signaling pathways.
Cell Science at a Glance on the Web
Electronic copies of the full-size poster
insert are available in the online version of
this article (see www.biologists.com/jcs).
Files in several formats are provided and
may be downloaded for use as slides.
Neuroligi
u
in
N
NMDAR
CaMKII
GKAP
P
2+
2
+
(See
poster
insert)
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JOURNAL OF CELL SCIENCE 114 (7)
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