Long-term
potentiation
(LTP)
is
arguably
the
most
compelling
cellular
model
for
learning
and
memory.
While
mechanisms
underlying
induction
of
LTP
('learning')
are
well
understood,
maintenance
('memory')
has
remained
contentious
over
last
20
years.
Here,
we
find
that
Ca
Pharmacological Reviews,
Год журнала:
2021,
Номер
73(4), С. 1469 - 1658
Опубликована: Окт. 1, 2021
Many
physiologic
effects
of
l-glutamate,
the
major
excitatory
neurotransmitter
in
mammalian
central
nervous
system,
are
mediated
via
signaling
by
ionotropic
glutamate
receptors
(iGluRs).
These
ligand-gated
ion
channels
critical
to
brain
function
and
centrally
implicated
numerous
psychiatric
neurologic
disorders.
There
different
classes
iGluRs
with
a
variety
receptor
subtypes
each
class
that
play
distinct
roles
neuronal
functions.
The
diversity
iGluR
subtypes,
their
unique
functional
properties
roles,
has
motivated
large
number
studies.
Our
understanding
advanced
considerably
since
first
subunit
gene
was
cloned
1989,
research
focus
expanded
encompass
facets
biology
have
been
recently
discovered
exploit
experimental
paradigms
made
possible
technological
advances.
Here,
we
review
insights
from
more
than
3
decades
studies
an
emphasis
on
progress
occurred
past
decade.
We
cover
structure,
function,
pharmacology,
neurophysiology,
therapeutic
implications
for
all
assembled
subunits
encoded
18
genes.
SIGNIFICANCE
STATEMENT:
Glutamate
important
virtually
aspects
either
involved
mediating
some
clinical
features
neurological
disease
or
represent
target
treatment.
Therefore,
pharmacology
this
will
advance
our
many
at
molecular,
cellular,
system
levels
provide
new
opportunities
treat
patients.
Receptors
moving
in
and
out
of
the
synapse
The
number
neurotransmitter
receptors
their
spatial
organization
on
postsynaptic
site
is
a
central
determinant
synaptic
efficacy.
Sophisticated
techniques
to
visualize
track
movement
single
molecules
have
provided
us
with
profound
new
insights
into
these
dynamics.
We
now
know
that
undergo
movements
different
scales.
Groc
Choquet
review
our
present
understanding
mechanisms
regulate
glutamate
receptor
localization
clustering.
Receptor
are
fundamental
basic
function
participate
many
forms
plasticity.
Science
,
this
issue
p.
eaay4631
Genes & Diseases,
Год журнала:
2023,
Номер
11(1), С. 103 - 134
Опубликована: Март 24, 2023
Wnt
signaling
plays
a
major
role
in
regulating
cell
proliferation
and
differentiation.
The
ligands
are
family
of
19
secreted
glycoproteins
that
mediate
their
effects
via
binding
to
Frizzled
receptors
LRP5/6
coreceptors
transducing
the
signal
either
through
β-catenin
canonical
pathway
or
series
other
proteins
noncanonical
pathway.
Many
individual
components
both
have
additional
functions
throughout
body,
establishing
complex
interplay
between
pathways.
This
crosstalk
pathways
gives
vital
many
cellular
organ
processes.
Dysregulation
this
system
has
been
implicated
diseases
affecting
wide
array
systems,
including
cancer
embryological
defects,
can
even
cause
embryonic
lethality.
complexity
its
interacting
made
target
for
therapeutic
treatments.
However,
stimulatory
inhibitory
treatments
come
with
potential
risks
need
be
addressed.
review
synthesized
much
current
knowledge
on
pathway,
beginning
history
signaling.
It
thoroughly
described
different
variants
signaling,
canonical,
Wnt/PCP,
Wnt/Ca2+
Further
description
involved
each
involvement
Finally,
explained
various
processes
Nature,
Год журнала:
2023,
Номер
621(7977), С. 146 - 153
Опубликована: Авг. 30, 2023
Learning
and
memory
are
thought
to
require
hippocampal
long-term
potentiation
(LTP),
one
of
the
few
central
dogmas
molecular
neuroscience
that
has
stood
undisputed
for
more
than
three
decades
is
LTP
induction
requires
enzymatic
activity
Ca
Physiological Reviews,
Год журнала:
2023,
Номер
103(4), С. 2897 - 2945
Опубликована: Июнь 8, 2023
Ca
2+
/calmodulin-dependent
protein
kinase
II
(CaMKII)
and
long-term
potentiation
(LTP)
were
discovered
within
a
decade
of
each
other
have
been
inextricably
intertwined
ever
since.
However,
like
many
marriages,
it
has
had
its
up
downs.
Based
on
the
unique
biochemical
properties
CaMKII,
was
proposed
as
memory
molecule
before
any
physiological
linkage
made
to
LTP.
reviewed
here,
convincing
CaMKII
synaptic
physiology
behavior
took
decades.
New
technologies
critical
in
this
journey,
including
vitro
brain
slices,
mouse
genetics,
single-cell
molecular
pharmacological
reagents,
structure,
two-photon
microscopy,
new
investigators
attracted
by
exciting
challenge.
This
review
tracks
journey
assesses
state
marriage
40
years
on.
The
collective
literature
impels
us
propose
relatively
simple
model
for
involving
following
steps
that
drive
process:
1)
entry
through
N-methyl-d-aspartate
(NMDA)
receptors
activates
CaMKII.
2)
undergoes
autophosphorylation
resulting
constitutive,
-independent
activity
exposure
binding
site
NMDA
receptor
subunit
GluN2B.
3)
Active
translocates
postsynaptic
density
(PSD)
binds
cytoplasmic
C-tail
4)
CaMKII-GluN2B
complex
initiates
structural
rearrangement
PSD
may
involve
liquid-liquid
phase
separation.
5)
involves
PSD-95
scaffolding
protein,
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid
(AMPARs),
their
transmembrane
AMPAR-regulatory
(TARP)
auxiliary
subunits,
an
accumulation
AMPARs
underlies
potentiation.
6)
stability
modified
is
maintained
complex.
7)
By
process
exchange
or
interholoenzyme
phosphorylation
maintains
face
turnover.
There
are
important
proteins
participate
enlargement
spine
modulation
maintain
In
we
critically
discuss
data
underlying
steps.
As
will
become
clear,
some
these
more
firmly
grounded
than
others,
provide
suggestions
how
evidence
supporting
can
be
strengthened
or,
based
data,
replaced.
Although
long
one,
prospect
having
detailed
cellular
understanding
learning
at
hand.
Journal of Neurochemistry,
Год журнала:
2020,
Номер
154(2), С. 121 - 143
Опубликована: Янв. 24, 2020
Abstract
The
N
‐methyl‐
D
‐aspartate
receptors
(NMDARs)
are
ionotropic
glutamate
that
mediate
the
flux
of
calcium
(Ca
2+
)
into
post‐synaptic
compartment.
Ca
influx
subsequently
triggers
activation
various
intracellular
signalling
cascades
underpin
multiple
forms
synaptic
plasticity.
Functional
NMDARs
assembled
as
heterotetramers
composed
two
obligatory
GluN1
subunits
and
GluN2
or
GluN3
subunits.
Four
different
(GluN2A‐D)
present
throughout
central
nervous
system;
however,
they
differentially
expressed,
both
developmentally
spatially,
in
a
cell‐
synapse‐specific
manner.
Each
subunit
confers
with
distinct
ion
channel
properties
trafficking
pathways.
Regulated
membrane
is
dynamic
process
ultimately
determines
number
at
synapses,
controlled
by
subunit‐specific
interactions
regulatory
proteins.
Here
we
review
recent
progress
made
towards
understanding
molecular
mechanisms
regulate
GluN2‐containing
NMDARs,
focusing
on
roles
several
key
proteins
interact
via
their
carboxyl
termini.
image
Physiological Reviews,
Год журнала:
2020,
Номер
101(3), С. 1309 - 1370
Опубликована: Окт. 1, 2020
Posttranscriptional
gene
expression
including
splicing,
RNA
transport,
translation,
and
decay
provides
an
important
regulatory
layer
in
many
if
not
all
molecular
pathways.
Research
the
last
decades
has
positioned
RNA-binding
proteins
(RBPs)
right
center
of
posttranscriptional
regulation.
Here,
we
propose
interdependent
networks
RBPs
to
regulate
complex
pathways
within
central
nervous
system
(CNS).
These
are
involved
multiple
aspects
neuronal
development
functioning,
higher
cognition.
Therefore,
it
is
sufficient
unravel
individual
contribution
a
single
RBP
its
consequences
but
rather
study
understand
tight
interplay
between
different
RBPs.
In
this
review,
summarize
recent
findings
field
biology
discuss
Second,
emphasize
underlying
dynamics
network
how
might
key
processes
such
as
neurogenesis,
synaptic
transmission,
plasticity.
Importantly,
envision
that
dysfunction
specific
could
lead
perturbation
network.
This
would
have
direct
indirect
(compensatory)
effects
mRNA
binding
translational
control
leading
global
changes
cellular
programs
general
plasticity
particular.
focus
on
cause
neuropsychiatric
neurodegenerative
disorders.
Based
findings,
alterations
entire
account
for
phenotypic
dysfunctions
observed
diseases
neurodegeneration,
epilepsy,
autism
spectrum