Journal of Neuroscience,
Journal Year:
2007,
Volume and Issue:
27(26), P. 6995 - 7005
Published: June 27, 2007
The
molecular
basis
of
l-3,4-dihydroxyphenylalanine
(l-DOPA)-induced
dyskinesia
(LID),
one
the
major
hindrances
in
current
therapy
for
Parkinson9s
disease,
is
still
unclear.
We
show
that
attenuation
cAMP
signaling
medium
spiny
neurons
striatum,
achieved
by
genetic
inactivation
dopamine
and
cAMP-regulated
phosphoprotein
32
kDa
(DARPP-32),
reduces
LID.
also
that,
dyskinetic
mice,
sensitized
cAMP/cAMP-dependent
protein
kinase/DARPP-32
leads
to
phosphorylation/activation
extracellular
signal-regulated
kinases
1
2
(ERK1/2).
increase
ERK1/2
phosphorylation
associated
with
results
activation
mitogen-
stress-activated
kinase-1
(MSK-1)
histone
H3,
two
downstream
targets
ERK
involved
transcriptional
regulation.
In
line
these
observations,
we
found
c-Fos
expression
abnormally
elevated
striata
mice
affected
Persistent
enhancement
cascade
implicated
generation
Thus,
pharmacological
using
SL327
(α-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile),
an
inhibitor
mitogen-activated
kinase/ERK
kinase,
MEK,
during
chronic
l-DOPA
treatment
counteracts
induction
dyskinesia.
Together,
indicate
a
significant
proportion
abnormal
involuntary
movements
developed
response
are
attributable
hyperactivation
striatal
pathway
including
sequential
DARPP-32,
ERK1/2,
MSK-1,
H3.
Annual Review of Cell and Developmental Biology,
Journal Year:
2007,
Volume and Issue:
23(1), P. 613 - 643
Published: July 31, 2007
The
cellular
processes
that
govern
neuronal
function
are
highly
complex,
with
many
basic
cell
biological
pathways
uniquely
adapted
to
perform
the
elaborate
information
processing
achieved
by
brain.
This
is
particularly
evident
in
trafficking
and
regulation
of
membrane
proteins
from
synapses,
which
can
be
a
long
distance
away
body
number
thousands.
neurotransmitter
receptors,
such
as
AMPA-type
glutamate
receptors
(AMPARs),
major
excitatory
brain,
crucial
mechanism
for
modulation
synaptic
transmission.
levels
AMPARs
at
synapses
very
dynamic,
it
these
plastic
changes
thought
underlie
storage
Thus,
understanding
machinery
controls
AMPAR
will
critical
basis
behavior
well
neurological
diseases.
Here
we
describe
life
cycle
AMPARs,
their
biogenesis,
through
journey
synapse,
ultimately
demise,
discuss
how
this
process
essential
brain
function.
Frontiers in Molecular Neuroscience,
Journal Year:
2010,
Volume and Issue:
unknown
Published: Jan. 1, 2010
Since
its
discovery
almost
three
decades
ago,
the
secreted
neurotrophin
brain-derived
neurotrophic
factor
(BDNF)
has
been
firmly
implicated
in
differentiation
and
survival
of
neurons
CNS.
More
recently,
BDNF
also
emerged
as
an
important
regulator
synaptogenesis
synaptic
plasticity
mechanisms
underlying
learning
memory
adult
In
this
review
we
will
discuss
our
knowledge
about
multiple
intracellular
signalling
pathways
activated
by
BDNF,
role
long-term
formation
well
synaptogenesis.
We
show
that
maturation
cellular
localisation
ability
to
regulate
both
excitatory
inhibitory
synapses
CNS
may
result
conflicting
alterations
formation.
Lack
a
precise
which
influences
higher
cognitive
functions
complex
behaviours
constitute
severe
limitation
possibility
devise
BDNF-based
therapeutics
for
human
disorders
Proceedings of the National Academy of Sciences,
Journal Year:
2004,
Volume and Issue:
102(2), P. 491 - 496
Published: Dec. 17, 2004
Many
drugs
of
abuse
exert
their
addictive
effects
by
increasing
extracellular
dopamine
in
the
nucleus
accumbens,
where
they
likely
alter
plasticity
corticostriatal
glutamatergic
transmission.
This
mechanism
implies
key
molecular
alterations
neurons
which
both
and
glutamate
inputs
are
activated.
Extracellular
signal-regulated
kinase
(ERK),
an
enzyme
important
for
long-term
synaptic
plasticity,
is
a
good
candidate
playing
such
role.
Here,
we
show
mouse
that
d
-amphetamine
activates
ERK
subset
medium-size
spiny
dorsal
striatum
through
combined
action
NMDA
D1-dopamine
receptors.
Activation
or
widely
abused
drugs,
including
cocaine,
nicotine,
morphine,
Δ
9
-tetrahydrocannabinol
was
absent
mice
lacking
dopamine-
cAMP-regulated
phosphoprotein
M
r
32,000
(DARPP-32).
The
cocaine
on
activation
striatum,
but
not
prefrontal
cortex,
were
prevented
point
mutation
Thr-34,
DARPP-32
residue
specifically
involved
protein
phosphatase-1
inhibition.
Regulation
occurred
upstream
at
level
striatal-enriched
tyrosine
phosphatase
(STEP).
Blockade
pathway
altered
locomotor
sensitization
induced
single
injection
psychostimulants,
demonstrating
functional
relevance
this
regulation.
Thus,
ERK,
multilevel
phosphatase-controlled
mechanism,
functions
as
detector
coincidence
signals
converging
striatal
critical
long-lasting
abuse.
Journal of Neuroscience,
Journal Year:
2005,
Volume and Issue:
25(49), P. 11288 - 11299
Published: Dec. 7, 2005
Dendritic
arborization
and
spine
formation
are
critical
for
the
functioning
of
neurons.
Although
many
proteins
have
been
identified
recently
as
regulators
dendritic
morphogenesis,
intracellular
signaling
pathways
that
control
these
processes
not
well
understood.
Here
we
report
Ras–phosphatidylinositol
3-kinase
(PI3K)–Akt–mammalian
target
rapamycin
(mTOR)
pathway
plays
pivotal
roles
in
regulation
aspects
dendrite
formation.
Whereas
PI3K–Akt–mTOR
alone
controlled
soma
size,
a
coordinated
activation
together
with
Ras-mitogen-activated
protein
kinase
was
required
increasing
complexity.
Chronic
inhibition
PI3K
or
mTOR
reduced
size
complexity,
density
filopodia
spines,
whereas
short-term
promoted
mushroom-shaped
spines
on
cells
expressing
constitutively
active
mutants
Ras,
PI3K,
Akt,
treated
upstream
activator
BDNF.
Together,
our
data
underscore
central
role
spatiotemporally
regulated
key
cell
survival
growth
trophic
development
shape.