Science Signaling,
Год журнала:
2015,
Номер
8(408)
Опубликована: Дек. 22, 2015
The
Ca(2+)
release-activated
channel
mediates
influx
in
a
plethora
of
cell
types,
thereby
controlling
diverse
cellular
functions.
complex
is
composed
stromal
interaction
molecule
1
(STIM1),
an
endoplasmic
reticulum
Ca(2+)-sensing
protein,
and
Orai1,
plasma
membrane
channel.
Channels
STIM1
Orai1
mediate
even
at
low
extracellular
concentrations.
We
investigated
whether
the
activity
adapted
to
different
environmental
used
homology
modeling
molecular
dynamics
simulations
predict
presence
Ca(2+)-accumulating
region
(CAR)
pore
entrance
Orai1.
Furthermore,
proteins
with
mutations
CAR,
along
live-cell
experiments,
or
electrophysiological
recordings
transient,
electrostatic
loop3
interacting
loop1
(the
site
CAR)
determined
that
CAR
enhanced
permeation
most
efficiently
external
Consistent
these
results,
cells
expressing
mutants
exhibited
impaired
gene
expression
stimulated
by
Ca(2+)-activated
transcription
factor
nuclear
activated
T
(NFAT).
propose
architecture
close
proximity
selectivity
filter,
which
enables
Ca(2+)-selective
ion
permeation,
enhances
local
concentration
maintain
Ca(2+)-dependent
regulation
environments
relatively
Ca(2+)concentrations.
Physiology,
Год журнала:
2017,
Номер
32(4), С. 332 - 342
Опубликована: Июнь 15, 2017
In
this
review
article,
we
discuss
the
different
gene
products
and
translational
variants
of
ORAI
proteins
their
contribution
to
makeup
native
calcium-conducting
channels
with
distinct
compositions
modes
activation.
We
also
regulation
these
calcium
impact
on
downstream
cellular
signaling
controlling
important
physiological
functions.
The Journal of Physiology,
Год журнала:
2018,
Номер
596(14), С. 2681 - 2698
Опубликована: Янв. 25, 2018
Cytotoxic
T
lymphocytes
(CTLs)
and
natural
killer
(NK)
cells
are
required
to
eliminate
cancer
cells.
We
analysed
the
Ca2+
dependence
of
CTL
NK
cell
cytotoxicity
found
that
in
particular
CTLs
have
a
very
low
optimum
[Ca2+
]i
(between
122
334
nm)
]o
23
625
μm)
for
efficient
elimination,
well
below
blood
plasma
levels.
As
predicted
from
these
results,
partial
down-regulation
channel
Orai1
paradoxically
increases
perforin-dependent
killing.
Lytic
granule
release
at
immune
synapse
between
has
compatible
with
this
killing,
whereas
migration
is
slightly
higher
proliferation
monotonously
increasing
.
propose
inhibition
signals
by
specific
blockers
submaximal
concentrations
could
contribute
tumour
elimination.Cytotoxic
protect
human
body
against
cancer.
key
metabolic
factor
lymphocyte
function
homeostasis.
bell-shaped
an
elimination
rather
(23-625
(122-334
nm).
This
finding
predicts
should
increase
(rather
than
decrease)
μm.
tested
hypothesis
indeed
siRNA
efficiency
two
mechanisms
may
account
killing:
(1)
velocity
persistence
moderate
500
1000
μm
CTLs,
(2)
lytic
increased
146
compared
3
or
800
μm,
It
been
demonstrated
many
types
Orai1-dependent
enhance
proliferation.
decrease
activity
selective
microenvironment
efficiently
reduce
growth
simultaneously
decreasing
Molecular Pharmacology,
Год журнала:
2015,
Номер
88(3), С. 572 - 578
Опубликована: Июль 16, 2015
Signaling
by
G-protein-coupled
receptors
is
often
considered
a
uniform
process,
whereby
homogeneously
activated
proportion
of
randomly
distributed
are
under
equilibrium
conditions
and
produce
homogeneous,
steady-state
intracellular
signals.
While
this
may
be
the
case
in
some
biologic
systems,
example
rhodopsin
with
its
strictly
local
single-quantum
mode
function
shows
that
homogeneity
space
time
cannot
general
property
systems.
Recent
work
has
now
revealed
many
other
systems
where
such
simplicity
does
not
prevail.
Instead,
plethora
mechanisms
allows
much
more
complex
patterns
receptor
activation
signaling:
different
protein-protein
interaction;
temporal
changes
nonequilibrium
conditions;
localized
activation;
second
messenger
generation
degradation-all
which
shape
receptor-generated
signals
permit
creation
multiple
signal
types.
Here,
we
review
evidence
for
pleiotropic
signaling
time.
Nature Communications,
Год журнала:
2015,
Номер
6(1)
Опубликована: Сен. 24, 2015
Abstract
The
endoplasmic
reticulum
(ER)
Ca
2+
sensor,
STIM1,
becomes
activated
when
ER-stored
is
depleted
and
translocates
into
ER–plasma
membrane
junctions
where
it
tethers
activates
Orai1
entry
channels.
dimeric
STIM1
protein
contains
a
small
STIM-Orai-activating
region
(SOAR)—the
minimal
sequence
sufficient
to
activate
Since
SOAR
itself
dimer,
we
constructed
concatemer–dimers
introduced
mutations
at
F394,
which
critical
for
coupling
activation.
F394H
mutation
in
both
monomers
completely
blocks
dimer
function,
but
only
one
of
the
has
no
effect
on
binding
or
This
reveals
an
unexpected
unimolecular
between
argues
against
recent
evidence
suggesting
interaction
two
adjacent
channel
subunits.
model
predicts
that
dimers
may
be
involved
crosslinking
channels
with
implications
kinetics
localization
opening.
Cell Reports,
Год журнала:
2018,
Номер
23(2), С. 522 - 534
Опубликована: Апрель 1, 2018
Ca2+
entry
mediated
by
the
calcium
channel,
Orai1,
provides
critical
signals
that
regulate
cell
function.
The
ER-Ca2+
sensor
protein,
STIM1,
recruits
and
strongly
activates
Orai1
within
ER-PM
junctions.
STIM2
is
a
poor
activator
of
its
physiological
role
not
well
understood.
Herein,
we
report
crucial
function
for
in
inducing
activated
conformation
STIM1.
By
using
conformational
sensors
together
with
protein
interaction
functional
studies,
show
constitutively
localized
junctions
store
replete
cells.
Importantly,
traps
STIM1
triggers
remodeling
C
terminus,
causing
STIM1/Orai1
coupling
enhancement
cells
relatively
high
ER-[Ca2+].
increase
controls
Ca2+-dependent
transcription
factor,
NFAT,
activation
at
low
[agonist].
Our
findings
reveal
modulates
to
tune
fidelity
receptor-evoked
signaling
response
Molecular Cell,
Год журнала:
2016,
Номер
64(4), С. 746 - 759
Опубликована: Ноя. 1, 2016
Excitation-transcription
coupling,
linking
stimulation
at
the
cell
surface
to
changes
in
nuclear
gene
expression,
is
conserved
throughout
eukaryotes.
How
closely
related
coexpressed
transcription
factors
are
differentially
activated
remains
unclear.
Here,
we
show
that
two
Ca2+-dependent
factor
isoforms,
NFAT1
and
NFAT4,
require
distinct
sub-cellular
InsP3
Ca2+
signals
for
physiologically
sustained
activation.
stimulated
by
sub-plasmalemmal
microdomains,
whereas
NFAT4
additionally
requires
mobilization
from
inner
envelope
receptors.
rephosphorylated
(deactivated)
more
slowly
than
both
cytoplasm
nucleus,
enabling
a
prolonged
activation
phase.
Oscillations
cytoplasmic
Ca2+,
long
considered
physiological
form
of
signaling,
play
no
role
activating
either
NFAT
protein.
Instead,
effective
tightly
linked
oscillations
Ca2+.
Our
results
how
expression
can
be
controlled
coincident
yet
geographically
signals,
generated
freely
diffusible
message.