G-protein-coupled
receptor
30
(GPR30)
is
a
bicarbonate
that
plays
vital
role
in
cellular
responses
to
extracellular
pH
and
ion
homeostasis.
Despite
its
significance,
the
mechanisms
by
which
GPR30
interacts
with
ions
remain
elusive.
There
no
consensus
on
drug
targets
GPR30,
difficulty
pharmacological
analysis
has
limited
biological
discovery
researches
GPR30.
Here,
we
present
cryo-electron
microscopy
structure
of
human
presence
at
3.2
Å
resolution.
Our
reveals
unique
pockets
critical
residues
for
binding
activation.
Functional
assays
demonstrate
mutations
these
impair
bicarbonate-induced
activation,
underscoring
their
importance
function.
This
study
also
provides
insights
into
G-protein
coupling,
highlighting
structural
divergence
between
other
GPCRs.
findings
not
only
advance
understanding
homeostasis
but
pave
way
development
high-affinity
drugs
targeting
therapeutic
interventions
diseases
associated
acid-base
imbalance.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2023,
Volume and Issue:
unknown
Published: March 21, 2023
ABSTRACT
The
canonical
view
of
G
protein-coupled
receptor
(GPCR)
function
is
that
trafficking
tightly
coupled
to
signaling.
GPCRs
remain
on
the
plasma
membrane
(PM)
at
cell
surface
until
they
are
activated,
after
which
desensitized
and
internalized
into
endosomal
compartments.
This
presents
an
interesting
context
for
proton-sensing
because
more
likely
be
activated
in
acidic
compartments
than
PM.
Here
we
show
prototypical
proton-sensor
GPR65
fully
uncoupled
from
signaling,
unlike
other
known
mammalian
GPCRs.
localized
early
late
endosomes,
where
signal
steady
state,
irrespective
extracellular
pH.
Acidic
environments
stimulated
signaling
PM
a
dose-dependent
manner,
although
was
still
required
full
response.
Receptor
mutants
were
incapable
activating
cAMP
trafficked
normally,
internalized,
Our
results
constitutively
active
suggest
model
changes
pH
reprograms
spatial
pattern
biases
location
surface.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: April 22, 2024
Abstract
Cancer
and
inflammation
are
associated
with
vascular
diseases
that
affect
endothelial
cells
(ECs)
alter
gene
expression.
We
aimed
at
understanding
whether
the
site
Y
685
in
cytoplasmic
domain
of
VE-cadherin
triggers
epigenetic
programming
vivo
.
Using
our
knock-in
mice
carrying
F
mutation,
RNA
sequencing
from
lung
ECs
identified
884
differentially
expressed
genes
(DEG)
involved
processes
such
as
cell-cell
adhesion,
development,
angiogenesis.
The
30
DEGs
include
22
down-regulated
(genes
encoding
cell
signalling
enzymes,
anion
transport
lipid
metabolism)
8
up-regulated
genes,
including
endothelial-specific
S1PR1.
Analysis
VEGF/VEGFR2
signaling
pathway
shows
a
significant
decrease
expression
pY
1173
VEGFR2
whereas
VEGF
remains
constant,
this
was
consistent
impaired
migration,
proliferation
protrusive
properties
vitro
Co-immunoprecipitation
experiments
showed
c-Src
F-VE-cadherin
association
which
enhanced
KI
compared
to
WT,
resulting
increased
phosphorylation
731
As
consequence,
its
partner
β-catenin
translocates
nucleus.
CHIPS
assay
FOXF1
binds
s1pr1
promoter,
leading
In
vivo,
vasculature,
process
vessel
wall
thickness
reduced
fibrosis.
Overall,
findings
provide
novel
transcriptomic
profile
triggered
by
for
potential
insights
into
therapeutic
targets
envisage
normalisation
tumor
vasculature.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: May 19, 2024
Abstract
G-protein-coupled
receptor
30
(GPR30)
is
a
bicarbonate
that
plays
vital
role
in
cellular
responses
to
extracellular
pH
and
ion
homeostasis.
Despite
its
significance,
the
mechanisms
by
which
GPR30
interacts
with
ions
remain
elusive.
There
no
consensus
on
drug
targets
GPR30,
difficulty
pharmacological
analysis
has
limited
biological
discovery
researches
GPR30.
Here,
we
present
cryo-electron
microscopy
structure
of
human
presence
at
3.2
Å
resolution.
Our
reveals
unique
pockets
critical
residues
for
binding
activation.
Functional
assays
demonstrate
mutations
these
impair
bicarbonate-induced
activation,
underscoring
their
importance
function.
This
study
also
provides
insights
into
G-protein
coupling,
highlighting
structural
divergence
between
other
GPCRs.
findings
not
only
advance
understanding
homeostasis
but
pave
way
development
high-affinity
drugs
targeting
therapeutic
interventions
diseases
associated
acid-base
imbalance.
G-protein-coupled
receptor
30
(GPR30)
is
a
bicarbonate
that
plays
vital
role
in
cellular
responses
to
extracellular
pH
and
ion
homeostasis.
Despite
its
significance,
the
mechanisms
by
which
GPR30
interacts
with
ions
remain
elusive.
There
no
consensus
on
drug
targets
GPR30,
difficulty
pharmacological
analysis
has
limited
biological
discovery
researches
GPR30.
Here,
we
present
cryo-electron
microscopy
structure
of
human
presence
at
3.2
Å
resolution.
Our
reveals
unique
pockets
critical
residues
for
binding
activation.
Functional
assays
demonstrate
mutations
these
impair
bicarbonate-induced
activation,
underscoring
their
importance
function.
This
study
also
provides
insights
into
G-protein
coupling,
highlighting
structural
divergence
between
other
GPCRs.
findings
not
only
advance
understanding
homeostasis
but
pave
way
development
high-affinity
drugs
targeting
therapeutic
interventions
diseases
associated
acid-base
imbalance.
