IntechOpen eBooks,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Dec. 6, 2024
The
aim
of
this
chapter
is
to
delve
comprehensively
into
ATP-sensitive
potassium
(KATP)
channel,
which
a
ubiquitous
class
ion
channels
located
in
the
biological
membrane
sense
intracellular
nucleotide
(ATP/ADP)
concentration
and
mediate
efflux
various
cell
types
(and
mitochondria),
thus
functions
as
link
between
metabolic
state
excitability.
This
mainly
includes
five
parts:
road
discovery
KATP
protein
subunit
composition
pharmacology
physiological
pathological
roles
with
particular
emphasis
on
pancreas,
heart,
vascular
smooth
muscles,
nervous
system.
Nature Communications,
Journal Year:
2024,
Volume and Issue:
15(1)
Published: March 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
The Journal of General Physiology,
Journal Year:
2022,
Volume and Issue:
155(1)
Published: Nov. 9, 2022
Gated
by
intracellular
ATP
and
ADP,
ATP-sensitive
potassium
(KATP)
channels
couple
cell
energetics
with
membrane
excitability
in
many
types,
enabling
them
to
control
a
wide
range
of
physiological
processes
based
on
metabolic
demands.
The
KATP
channel
is
complex
four
subunits
from
the
Kir
family,
Kir6.1
or
Kir6.2,
sulfonylurea
receptor
subunits,
SUR1,
SUR2A,
SUR2B,
ATP-binding
cassette
(ABC)
transporter
family.
Dysfunction
underlies
several
human
diseases.
importance
these
health
disease
has
made
attractive
drug
targets.
How
interact
one
another
how
ligands
regulate
activity
have
been
long-standing
questions
field.
In
past
5
yr,
steady
stream
high-resolution
structures
published
using
single-particle
cryo-electron
microscopy
(cryo-EM).
Here,
we
review
advances
bring
our
understanding
regulation
pharmacological
ligands.
Pancreatic
K
ATP
channel
trafficking
defects
underlie
congenital
hyperinsulinism
(CHI)
cases
unresponsive
to
the
opener
diazoxide,
mainstay
medical
therapy
for
CHI.
Current
clinically
used
inhibitors
have
been
shown
act
as
pharmacochaperones
and
restore
surface
expression
of
mutants;
however,
their
therapeutic
utility
impaired
CHI
is
hindered
by
high-affinity
binding,
which
limits
functional
recovery
rescued
channels.
Recent
structural
studies
channels
employing
cryo-electron
microscopy
(cryoEM)
revealed
a
promiscuous
pocket
where
several
known
bind.
The
knowledge
provides
framework
discovering
with
desired
reversible
inhibitory
effects
permit
Using
an
AI-based
virtual
screening
technology
AtomNet®
followed
validation,
we
identified
novel
compound,
termed
Aekatperone,
exhibits
chaperoning
on
mutations.
Aekatperone
reversibly
inhibits
activity
half-maximal
concentration
(IC
50
)
∼
9
μM.
Mutant
cell
showed
upon
washout
compound.
CryoEM
structure
bound
distinct
binding
features
compared
high
affinity
inhibitor
pharmacochaperones.
Our
findings
unveil
pharmacochaperone
enabling
promising
caused
defects.
Pancreatic
K
ATP
channel
trafficking
defects
underlie
congenital
hyperinsulinism
(CHI)
cases
unresponsive
to
the
opener
diazoxide,
mainstay
medical
therapy
for
CHI.
Current
clinically
used
inhibitors
have
been
shown
act
as
pharmacochaperones
and
restore
surface
expression
of
mutants;
however,
their
therapeutic
utility
trafficking-impaired
CHI
is
hindered
by
high
affinity
binding,
which
limits
functional
recovery
rescued
channels.
Recent
structural
studies
channels
employing
cryo-electron
microscopy
(cryoEM)
revealed
a
promiscuous
pocket
where
several
known
bind.
The
knowledge
provides
framework
discovering
with
desired
reversible
inhibitory
effects
permit
Using
an
AI-based
virtual
screening
technology
AtomNet
followed
validation,
we
identified
novel
compound,
termed
Aekatperone,
exhibits
chaperoning
on
mutations.
Aekatperone
reversibly
inhibits
activity
half-maximal
concentration
(IC
50
)
~9
μM.
Mutant
cell
showed
upon
washout
compound.
CryoEM
structure
bound
distinct
binding
features
compared
inhibitor
pharmacochaperones.
Our
findings
unveil
pharmacochaperone
enabling
promising
caused
defects.
The Journal of Membrane Biology,
Journal Year:
2025,
Volume and Issue:
unknown
Published: March 26, 2025
Abstract
This
work
describes
a
computer
study
that
looks
at
how
different
amounts
of
cholesterol
(0%,
25%,
and
50%)
in
cell
membranes
change
the
relationship
between
ATP
K
channel.
could
explain
why
pancreatic
beta-cells
secrete
insulin
differently.
We
use
simulations
molecular
dynamics,
calculations
binding
free
energy,
an
integrated
oscillator
model
to
look
electrical
activity
beta-cells.
There
is
need
for
this
kind
multiscale
approach
right
now
because
plays
part
metabolic
syndrome
early
type
2
diabetes.
Our
results
showed
increase
concentration
membrane
affects
electrostatic
interactions
channel,
especially
with
charged
residues
site.
Cholesterol
can
influence
properties
membrane,
including
its
local
charge
distribution
near
environment
around
ATP-binding
site,
increasing
affinity
channel
as
our
indicated
from
0
25
50%
(−
141
−
113
kJ/mol,
respectively).
Simulating
channels
beta-cell
indicates
even
minimal
produce
hyperinsulism.
The
answers
important
research
question
about
structure
function
and,
turn,
releases
common
feature
stages
Graphical
The Journal of Physiology,
Journal Year:
2025,
Volume and Issue:
unknown
Published: May 31, 2025
Abstract
First
identified
40
years
ago
in
cardiac
myocytes,
ATP‐sensitive
potassium
(K
ATP
)
channels
have
been
found
almost
all
excitable
tissues,
with
paradigmatic
inhibition
by
and
activation
ADP
underlying
their
physiological
role
coupling
cellular
metabolism
to
electrical
activity.
Cloning
of
the
genes,
30
ago,
revealed
unique
assembly
as
four
Kir6.x
pore‐forming
subunit
proteins
sulfonylurea
receptor
(SURx)
has
since
led
discovery
a
spectrum
monogenic
diseases
resulting
from
gain‐
(GOF)
or
loss‐of‐function
(LOF)
mutations,
turn
leading
recognition
novel
roles
pathophysiological
consequences
throughout
body.
With
this
perspective,
lecture
represents
personal
view
these
discoveries
potential
for
future
insights.
image
Journal of Chemical Information and Modeling,
Journal Year:
2023,
Volume and Issue:
63(6), P. 1806 - 1818
Published: Feb. 6, 2023
Commonly
used
techniques,
such
as
CryoEM
or
X-ray,
are
not
able
to
capture
the
structural
reorganizations
of
disordered
regions
proteins
(IDR);
therefore,
it
is
difficult
assess
their
functions
in
based
exclusively
on
experiments.
To
fill
this
gap,
we
computational
molecular
dynamics
(MD)
simulation
methods
IDR
and
trace
biological
function-related
interactions
Kir6.2/SUR1
potassium
channel.
This
ATP-sensitive
octameric
complex,
one
critical
elements
insulin
secretion
process
human
pancreatic
β-cells,
has
four
five
large,
fragments.
Using
unique
MD
simulations
full
channel
present
an
in-depth
analysis
discuss
possible
they
could
have
system.
Our
results
confirmed
crucial
role
N-terminus
Kir6.2
fragment
L0-loop
SUR1
protein
transfer
mechanical
signals
between
domains
that
trigger
release.
Moreover,
show
presence
IDRs
affects
natural
ligand
binding.
research
takes
us
step
further
toward
understanding
action
vital
complex.