The
voltage-gated
potassium
channel
Kv1.3
plays
a
crucial
role
in
T-cell
activation
and
is
considered
promising
target
for
the
treatment
of
autoimmune
diseases.However,
lack
reliable
antibodies
has
prevented
its
accurate
detection
study
under
endogenous
conditions,
so
that
most
published
studies
have
been
conducted
heterologous
systems.To
address
this
limitation,
we
engineered
Jurkat
line
expressing
channels
tagged
with
signal
peptide
to
investigate
expression
localization
native
channels,
their
associated
T
cell
physiological
responses.Using
CRISPR-Cas9
tool,
inserted
Flag-Myc
at
C
terminus
KCNA3
gene.Basal
activated
were
assessed
through
western
blot
analysis
imaging
techniques.Surprisingly,
besides
canonical
(54
KDa),
identified
two
additional
isoforms
distinct
N
termini:
longer
isoform
(70
KDa)
truncated
(43
KDa).All
three
showed
upregulation
after
activation.Our
focus
was
on
characterizing
(short
form,
SF)
as
it
had
not
previously
described
could
be
present
available
Kv1.3-/-mouse
models.Overexpressing
SF
HEK
cells
generated
Kv1.3-like
currents
smaller
amplitudes,
which,
unlike
Kv1.3,
did
induce
proliferation.To
explore
system,
both
knockout
clone
only
isoform.While
localized
primarily
plasma
membrane,
remained
intracellular,
accumulating
perinuclearly.Consequently,
lacked
currents,
exhibited
depolarized
resting
membrane
potential
(EM),
reduced
Ca
2+
influx,
diminished
increases
intracellular
calcium
([Ca
]i)
upon
stimulation.Functional
characterization
these
revealed
differential
contributions
signaling
pathways
involved
immunological
synapse
formation.In
conclusion,
alternative
translation
initiation
generates
least
functional
roles.Importantly,
some
functions
do
require
formation
by
proteins.
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Март 20, 2024
Abstract
ATP-sensitive
potassium
(K
ATP
)
channels,
composed
of
four
pore-lining
Kir6.2
subunits
and
regulatory
sulfonylurea
receptor
1
(SUR1)
subunits,
control
insulin
secretion
in
pancreatic
β-cells.
K
channel
opening
is
stimulated
by
PIP
2
inhibited
ATP.
Mutations
that
increase
reduce
inhibition
cause
neonatal
diabetes.
Although
considerable
evidence
has
implicated
a
role
for
function,
previously
solved
open-channel
structures
have
lacked
bound
,
mechanisms
which
regulates
channels
remain
unresolved.
Here,
we
report
the
cryoEM
structure
harboring
diabetes
mutation
Kir6.2-Q52R,
open
conformation,
to
amphipathic
molecules
consistent
with
natural
C18:0/C20:4
long-chain
PI(4,5)P
at
two
adjacent
binding
sites
between
SUR1
Kir6.2.
The
canonical
site
conserved
among
-gated
Kir
channels.
non-canonical
forms
interface
SUR1.
Functional
studies
demonstrate
both
determine
activity.
pore
associated
twist
cytoplasmic
domain
rotation
N-terminal
transmembrane
SUR1,
widens
inhibitory
pocket
disfavor
binding.
conformation
particularly
stabilized
Kir6.2-Q52R
residue
through
cation-π
bonding
SUR1-W51.
Together,
these
results
uncover
cooperation
gating,
explain
antagonistic
regulation
ATP,
provide
putative
mechanism
stabilizes
an
Frontiers in Endocrinology,
Год журнала:
2023,
Номер
14
Опубликована: Март 28, 2023
Congenital
hyperinsulinism
(CHI)
is
the
most
common
cause
of
persistent
hypoglycemia
in
infancy/childhood
and
a
serious
condition
associated
with
severe
recurrent
attacks
due
to
dysregulated
insulin
secretion.
Timely
diagnosis
effective
treatment
are
crucial
prevent
that
may
lead
life-long
neurological
complications.
In
pancreatic
β-cells,
adenosine
triphosphate
(ATP)-sensitive
K
Molecules,
Год журнала:
2024,
Номер
29(8), С. 1904 - 1904
Опубликована: Апрель 22, 2024
Diabetes
mellitus
(DM)
represents
a
problem
for
the
healthcare
system
worldwide.
DM
has
very
serious
complications
such
as
blindness,
kidney
failure,
and
cardiovascular
disease.
In
addition
to
bad
socioeconomic
impacts,
it
influences
patients
their
families
communities.
The
global
costs
of
its
are
huge
expected
rise
by
year
2030.
is
caused
genetic
environmental
risk
factors.
Genetic
testing
will
aid
in
early
diagnosis
identification
susceptible
individuals
or
populations
using
ATP-sensitive
potassium
(KATP)
channels
present
different
tissues
pancreas,
myocardium,
myocytes,
nervous
tissues.
respond
concentrations
blood
sugar,
stimulation
hormones,
ischemic
conditions.
pancreatic
cells,
they
regulate
secretion
insulin
glucagon.
Mutations
KCNJ11
gene
that
encodes
Kir6.2
protein
(a
major
constituent
KATP
channels)
were
reported
be
associated
with
Type
2
DM,
neonatal
diabetes
(NDM),
maturity-onset
young
(MODY).
harbors
binding
sites
ATP
phosphatidylinositol
4,5-diphosphate
(PIP2).
inhibits
channel,
while
(PIP2)
activates
it.
A
mutation
at
tyrosine330
(Y330)
was
demonstrated
reduce
inhibition
predisposes
NDM.
this
study,
we
examined
effect
mutations
on
structure
bioinformatics
tools
molecular
dynamic
simulations
(SIFT,
PolyPhen,
SNAP2,
PANTHER,
PhD&SNP,
SNP&Go,
I-Mutant,
MuPro,
MutPred,
ConSurf,
HOPE,
GROMACS).
Our
results
indicated
M199R,
R201H,
R206H,
Y330H
influence
function
therefore
may
cause
DM.
We
conclude
MD
useful
techniques
predict
effects
structure.
addition,
variant
These
require
further
verification
protein–protein
interactions,
function,
case-control
studies.
Biomedicine & Pharmacotherapy,
Год журнала:
2024,
Номер
177, С. 116986 - 116986
Опубликована: Июнь 20, 2024
Apigenin,
a
natural
bioflavonoid,
is
reported
as
an
anti-diabetic
agent
since
it
possesses
the
ability
to
inhibit
α-glucosidase
activity,
cause
stimulation
of
insulin
action
and
secretion,
manage
ROS,
prevent
diabetes
complications.
Apigenin
was
identified
new
secretagogue
that
enhances
glucose-stimulated
secretion
seems
like
better
antidiabetic
drug
candidate.
Here
we
explored
insulinotropic
mechanism(s)
apigenin
in
vitro
mice
islets
vivo
diabetic
rats.
Journal of Traditional and Complementary Medicine,
Год журнала:
2024,
Номер
14(5), С. 494 - 500
Опубликована: Янв. 11, 2024
In
Ayurveda,
every
individual
is
believed
to
possess
a
unique
entity
known
as
Prakriti,
which
distinguishes
them
from
others
physically,
physiologically,
and
psychologically.
This
also
determines
an
individual's
response
particular
stimulus,
it
that
such
responses
are
not
solely
determined
by
genetics.
The
present
research
aims
validate
the
Ayurvedic
concept
of
Prakriti
modern
molecular
perspective
strengthen
personalized
precise
treatment
approach.
A
study
was
conducted
investigate
role
KCNJ11gene
in
susceptibility
individuals
type
2
diabetes
mellitus
(T2DM)
with
their
metabolic
status.
involved
allele
mining
on
three
major
groups
-
Vata,
Pitta,
Kapha
112
patients
T2DM
healthy
individuals.
KCNJ11
gene,
responsible
for
insulin
secretion
membrane
pore
formation,
analyzed
determine
different
types
T2DM.
MutPred
tool
predicted
cause
disease-related
amino
acid
substitution.
According
study,
only
Pitta
were
diagnosed
diabetes,
while
all
control
group
protein
model
prepared,
changes
resulting
mutations
observed
each
sequence,
both
synonymous
non-synonymous
mutations.
Ultimately,
these
contributed
manifestation
Based
findings,
appears
may
experience
function
due
nonsynonymous
differences
acids
at
level.