G-protein
signaling
pathways
mediate
communication
across
cell
membranes.
The
first
steps
of
this
occur
at
the
membrane,
where
upon
receiving
an
external
signal
–the
binding
agonist
ligand–
membrane-embedded
G-Protein
Coupled
Receptor
adopts
a
conformation
recognized
by
cytoplasmatic
G
protein.
Whereas
specialized
GPCRs
sense
protons
from
extracellular
milieu,
thus
acting
as
pH
sensors
in
cells,
accumulating
evidence
suggests
that
sensitivity
might
be
common
to
distinct
GPCRs.
In
perspective
article
we
discuss
general
principles
protonation-coupled
protein
conformational
dynamics
and
how
these
apply
To
dissect
molecular
interactions
govern
GPCRs,
use
graph-based
algorithms
compute
graphs
hydrogen
bond
networks.
We
find
internal
H-bond
networks
contain
sites
structural
rearrangements
protonation
change
could
transmitted
throughout
Proton
bulk-exposed
clusters
titratable
sidechains
ensures
sensing
mechanism
is
robust.
Pflügers Archiv - European Journal of Physiology,
Год журнала:
2022,
Номер
474(8), С. 919 - 934
Опубликована: Май 5, 2022
Kidneys
are
central
in
the
regulation
of
multiple
physiological
functions,
such
as
removal
metabolic
wastes
and
toxins,
maintenance
electrolyte
fluid
balance,
control
pH
homeostasis.
In
addition,
kidneys
participate
systemic
gluconeogenesis
production
or
activation
hormones.
Acid-base
conditions
influence
all
these
functions
concomitantly.
Healthy
properly
coordinate
a
series
responses
face
acute
chronic
acid-base
disorders.
However,
injured
have
reduced
capacity
to
adapt
challenges.
Chronic
kidney
disease
patients
an
example
individuals
typically
exposed
progressive
acidosis.
Their
organisms
undergo
alterations
that
brake
large
detrimental
changes
homeostasis
several
parameters,
but
may
also
operate
further
drivers
damage.
disorders
lead
not
only
mechanisms
involved
balance
maintenance,
they
affect
other
tightly
wired
it.
this
review
article,
we
explore
basic
renal
activities
show
how
interconnected
cell
energy
metabolism
important
intracellular
activities.
These
intertwined
relationships
been
investigated
for
more
than
century,
modern
conceptual
organization
events
is
lacking.
We
propose
indissociably
interacts
with
pathways
drive
progression
disease,
inflammation
metabolism,
independent
etiology.
Biomedicines,
Год журнала:
2023,
Номер
11(12), С. 3229 - 3229
Опубликована: Дек. 6, 2023
Inflammatory
bowel
disease
(IBD)
is
a
lifelong
inflammatory
immune
mediated
disorder,
encompassing
Crohn's
(CD)
and
ulcerative
colitis
(UC);
however,
the
cause
specific
pathogenesis
of
IBD
yet
incompletely
understood.
Multiple
cytokines
produced
by
different
cell
types
results
in
complex
functional
networks
that
constitute
highly
regulated
messaging
network
signaling
pathways.
Applying
biological
mechanisms
underlying
at
single
omic
level,
technologies
genetic
engineering
enable
quantification
pattern
released
new
insights
into
cytokine
landscape
IBD.
We
focus
on
existing
literature
dealing
with
biology
pro-
or
anti-inflammatory
interactions
facilitate
cell-based
modulation
system
for
inflammation.
summarize
main
roles
substantial
related
to
homeostatic
tissue
functions
remodeling
IBD,
which
may
be
specifically
valuable
successful
cytokine-targeted
therapies
via
marketed
products.
Cytokines
their
receptors
are
validated
targets
multiple
therapeutic
areas,
we
review
current
strategies
intervention
developing
therapies.
New
biologics
have
shown
efficacy
last
few
decades
management
IBD;
unfortunately,
many
patients
nonresponsive
develop
therapy
resistance
over
time,
creating
need
novel
therapeutics.
Thus,
treatment
options
beyond
immune-modifying
anti-TNF
agents
combination
expanding
rapidly.
Further
studies
needed
fully
understand
response,
cytokines,
direct
pathogenetic
relevance
regarding
individually
tailored,
safe
efficient
targeted-biotherapeutics.
Nature Communications,
Год журнала:
2025,
Номер
16(1)
Опубликована: Янв. 11, 2025
G
protein-coupled
receptor
4
(GPR4)
belongs
to
the
subfamily
of
proton-sensing
GPCRs
(psGPCRs),
which
detect
pH
changes
in
extracellular
environment
and
regulate
diverse
physiological
responses.
GPR4
was
found
be
overactivated
acidic
tumor
microenvironment
as
well
inflammation
sites,
with
a
triad
residues
within
transmembrane
domain
identified
crucial
for
proton
sensing.
However,
3D
structure
remains
unknown,
roles
other
conserved
psGPCRs
are
not
understood.
Here
we
report
cryo-electron
microscopy
(cryo-EM)
structures
active
zebrafish
at
both
6.5
8.5,
each
highlighting
distribution
histidine
region.
Cell-based
assays
show
that
these
ionizable
moderately
influence
capacity
GPR4,
compared
more
significant
effects
residues.
Furthermore,
reveal
cluster
aromatic
orthosteric
pocket
may
propagate
signaling
intercellular
region
via
repacking
patch
central
This
study
provides
framework
future
functional
investigation
psGPCRs.
The
low
Here,
authors
cryo-EM
provide
insight
into
structural
features
sensing
mechanism.
AJP Cell Physiology,
Год журнала:
2022,
Номер
323(2), С. C400 - C414
Опубликована: Июнь 27, 2022
Local
acidification
is
a
common
feature
of
many
disease
processes
such
as
inflammation,
infarction,
or
solid
tumor
growth.
Acidic
pH
not
merely
sequela
but
contributes
to
recruitment
and
regulation
immune
cells,
modifies
metabolism
parenchymal,
modulates
fibrosis,
vascular
permeability,
oxygen
availability,
consumption,
invasiveness
impacts
on
cell
survival.
Thus,
multiple
pH-sensing
mechanisms
must
exist
in
cells
involved
these
processes.
These
sensors
play
important
roles
normal
physiology
pathophysiology,
hence
might
be
attractive
targets
for
pharmacological
interventions.
Among
the
mechanisms,
OGR1
(
GPR68),
GPR4
GPR4),
TDAG8
GPR65)
have
emerged
molecules.
G
protein-coupled
receptors
are
widely
expressed,
upregulated
inflammation
tumors,
sense
changes
extracellular
range
between
8
6,
modulating
key
biology,
fibrosis.
This
review
discusses
features
highlights
states
pathways
affected
by
their
activity.
Abstract
Increasing
numbers
of
studies
have
shown
that
tumor
cells
prefer
fermentative
glycolysis
over
oxidative
phosphorylation
to
provide
a
vast
amount
energy
for
fast
proliferation
even
under
oxygen‐sufficient
conditions.
This
metabolic
alteration
not
only
favors
cell
progression
and
metastasis
but
also
increases
lactate
accumulation
in
solid
tumors.
In
addition
serving
as
byproduct
glycolytic
cells,
plays
central
role
the
construction
acidic
immunosuppressive
microenvironment,
resulting
therapeutic
tolerance.
Recently,
targeted
drug
delivery
inherent
properties
nanomaterials
attracted
great
attention,
research
on
modulating
metabolism
based
enhance
antitumor
therapy
has
exploded.
this
review,
advanced
strategies
interfere
with
are
discussed,
including
inhibiting
anabolism,
promoting
catabolism,
disrupting
“lactate
shuttle”.
Furthermore,
recent
advances
combining
modulation
other
therapies,
chemotherapy,
immunotherapy,
photothermal
therapy,
reactive
oxygen
species‐related
etc.,
which
achieved
cooperatively
enhanced
outcomes,
summarized.
Finally,
foreseeable
challenges
prospective
developments
reviewed
future
development
field.
Science Immunology,
Год журнала:
2024,
Номер
9(100)
Опубликована: Окт. 18, 2024
Multiple
cancers,
including
colorectal
cancer
(CRC),
are
more
frequent
and
often
aggressive
in
individuals
with
obesity.
Here,
we
showed
that
macrophages
accumulated
within
tumors
of
patients
obesity
CRC
obese
mice
they
promoted
accelerated
tumor
growth.
These
changes
were
initiated
by
oleic
acid
accumulation
subsequent
cell–derived
production
driven
macrophage
signaling
through
the
acid-sensing
receptor
GPR65.
We
found
a
similar
role
for
GPR65
hepatocellular
carcinoma
(HCC)
mice.
Tumors
or
HCC
also
exhibited
increased
expression,
suggesting
mechanism
revealed
here
may
contribute
to
growth
range
obesity-associated
cancers
represent
potential
therapeutic
target.
Cancer Science,
Год журнала:
2024,
Номер
115(5), С. 1551 - 1563
Опубликована: Фев. 27, 2024
Cancer
tissues
exhibit
an
acidic
microenvironment
owing
to
the
accumulation
of
protons
and
lactic
acid
produced
by
cancer
inflammatory
cells.
To
examine
role
in
lymphatic
metastasis,
gene
expression
profiling
was
conducted
using
human
dermal
endothelial
cells
(HDLECs)
treated
with
a
low
pH
medium.
Microarray
set
enrichment
analysis
revealed
that
treatment
induced
inflammation-related
genes
HDLECs,
including
encoding
chemokines
adhesion
molecules.
Acid
treatment-induced
C-X3-C
motif
chemokine
ligand
1
(CX3CL1)
C-X-C
6
(CXCL6)
autocrinally
promoted
growth
tube
formation
HDLECs.
The
vascular
cell
molecule
(VCAM-1)
increased
HDLECs
after
time-dependent
manner,
which,
turn,
enhanced
their
melanoma
Among
various
acid-sensing
receptors,
basally
expressed
G
protein-coupled
receptor
4
(GPR4),
which
augmented
under
microenvironment.
induction
or
VCAM-1
conditions
attenuated
GPR4
knockdown
In
addition,
lymph
node
metastases
mouse
model
were
suppressed
administering
anti-VCAM-1
antibody
antagonist.
These
results
suggest
modifies
function
via
GPR4,
thereby
promoting
metastasis.
Acid-sensing
receptors
downstream
molecules
might
serve
as
preventive
therapeutic
targets
cancer.