Authorea (Authorea),
Journal Year:
2023,
Volume and Issue:
unknown
Published: Sept. 4, 2023
Biased
signaling
is
a
natural
result
of
GPCR
allosteric
function
and
should
be
expected
from
any
all
synthetic
agonists.
Therefore,
it
may
encountered
in
agonist
discovery
projects
must
considered
as
beneficial
(or
possible
detrimental)
feature
new
candidate
molecules.
While
bias
easily
detected
,
the
synoptic
nature
makes
translation
simple
vitro
to
complex
vivo
systems
problematic.
The
practical
outcome
this
difficulty
predicting
therapeutic
value
biased
due
failure
identified
agonism.
This
discussed
review
well
some
ways
forward
improve
process
better
exploit
powerful
pharmacologic
activity.
British Journal of Pharmacology,
Journal Year:
2024,
Volume and Issue:
181(9), P. 1345 - 1360
Published: Feb. 29, 2024
Biased
signalling
is
a
natural
result
of
GPCR
allosteric
function
and
should
be
expected
from
any
all
synthetic
agonists.
Therefore,
it
may
encountered
in
agonist
discovery
projects
must
considered
as
beneficial
(or
possible
detrimental)
feature
new
candidate
molecules.
While
bias
detected
easily,
the
synoptic
nature
makes
translation
simple
vitro
to
complex
vivo
systems
problematic.
The
practical
outcome
this
difficulty
predicting
therapeutic
value
biased
due
failure
identified
agonism.
This
discussed
review
well
some
ways
forward
improve
process
better
exploit
powerful
pharmacologic
mechanism.
Biomedicine & Pharmacotherapy,
Journal Year:
2024,
Volume and Issue:
177, P. 117009 - 117009
Published: June 21, 2024
Cyclic
adenosine
monophosphate
(cAMP)
is
a
key
second
messenger
that
regulates
signal
transduction
pathways
pivotal
for
numerous
biological
functions.
Intracellular
cAMP
levels
are
spatiotemporally
regulated
by
their
hydrolyzing
enzymes
called
phosphodiesterases
(PDEs).
It
has
been
shown
increased
in
the
central
nervous
system
(CNS)
promote
neuroplasticity,
neurotransmission,
neuronal
survival,
and
myelination
while
suppressing
neuroinflammation.
Thus,
elevating
through
PDE
inhibition
provides
therapeutic
approach
multiple
CNS
disorders,
including
sclerosis,
stroke,
spinal
cord
injury,
amyotrophic
lateral
traumatic
brain
Alzheimer's
disease.
In
particular,
of
cAMP-specific
PDE4
subfamily
widely
studied
because
its
high
expression
CNS.
So
far,
clinical
translation
full
inhibitors
hampered
dose-limiting
side
effects.
Hence,
focusing
on
signaling
cascades
downstream
activated
upon
presents
promising
strategy,
offering
novel
pharmacologically
safe
targets
treating
disorders.
Yet,
underlying
PDE(4)
remain
partially
elusive.
This
review
comprehensive
overview
existing
knowledge
regarding
mediators
induced
or
stimulators.
Furthermore,
we
highlight
gaps
future
perspectives
may
incentivize
additional
research
concerning
inhibition,
thereby
providing
approaches
Journal of Biological Chemistry,
Journal Year:
2024,
Volume and Issue:
300(3), P. 105756 - 105756
Published: Feb. 15, 2024
Heterotrimeric
G
proteins
(Gαβγ)
are
molecular
switches
that
relay
signals
from
7-transmembrane
receptors
located
at
the
cell
surface
to
cytoplasm.
The
function
of
these
is
so
intimately
linked
heterotrimeric
they
named
protein-coupled
(GPCRs),
showcasing
interdependent
nature
this
archetypical
receptor-transducer
axis
transmembrane
signaling
in
eukaryotes.
It
generally
assumed
activation
protein
occurs
exclusively
by
action
GPCRs,
but
idea
has
been
challenged
discovery
alternative
mechanisms
which
can
propagate
cell.
This
review
will
focus
on
a
general
principle
operates
without
direct
involvement
GPCRs.
mechanism
reviewed
here
mediated
class
regulators
defined
containing
an
evolutionarily
conserved
sequence
Gα-binding-and-activating
(GBA)
motif.
Using
best
characterized
with
GBA
motif
as
examples,
Gα-interacting
vesicle-associated
(GIV)/Girdin
and
dishevelled-associating
high
frequency
leucine
residues
(DAPLE),
cover
(i)
extracellular
cues
not
relayed
GPCRs
promote
coupling
motif-containing
proteins,
(ii)
structural
basis
for
how
motifs
interact
Gα
subunits
facilitate
signaling,
(iii)
relevance
different
cellular
pathological
processes,
including
cancer
birth
defects,
(iv)
strategies
manipulate
GBA-G
experimental
therapeutics
purposes,
development
rationally
engineered
chemical
probes.
Proceedings of the National Academy of Sciences,
Journal Year:
2025,
Volume and Issue:
122(17)
Published: April 22, 2025
Many
GPCRs
initiate
a
second
phase
of
G
protein-mediated
signaling
from
endosomes.
This
inherently
requires
the
GPCR
to
increase
cognate
protein
activity
on
endosome
surface.
s
-coupled
are
thought
achieve
this
by
internalizing
and
mediating
round
allosteric
coupling
proteins
membrane.
Here,
we
provide
evidence
that
μ-opioid
receptor
(MOR),
i
GPCR,
is
able
endosomal
in
different
way.
Leveraging
conformational
biosensors,
show
MOR
activation
triggers
transient
active-state
i/o
plasma
membrane
followed
prolonged
Contrary
paradigm,
however,
MOR-induced
endosomes
neither
internalization
nor
presence
activated
We
propose
distinct
additional
cellular
mechanism
communicated
through
trafficking
rather
than
its
activating
GPCR.
Chemical Reviews,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Feb. 25, 2025
Cell-surface
receptors
are
vital
for
controlling
numerous
cellular
processes
with
their
dysregulation
being
linked
to
disease
states.
Therefore,
it
is
necessary
develop
tools
study
and
the
signaling
pathways
they
control.
This
Review
broadly
describes
molecular
approaches
that
enable
1)
visualization
of
determine
localization
distribution;
2)
sensing
receptor
activation
permanent
readouts
as
well
in
real
time;
3)
perturbing
activity
mimicking
receptor-controlled
learn
more
about
these
processes.
Together,
have
provided
valuable
insight
into
fundamental
biology
helped
characterize
therapeutics
target
receptors.
Journal of Biological Chemistry,
Journal Year:
2023,
Volume and Issue:
300(1), P. 105497 - 105497
Published: Nov. 26, 2023
For
many
decades,
our
understanding
of
G
protein-coupled
receptor
(GPCR)
activity
and
cyclic
AMP
(cAMP)
signaling
was
limited
exclusively
to
the
plasma
membrane.
However,
a
growing
body
evidence
has
challenged
this
view
by
introducing
concept
endocytosis-dependent
GPCR
signaling.
This
emerging
paradigm
emphasizes
not
only
sustained
production
cAMP
but
also
its
precise
subcellular
localization,
thus
transforming
spatiotemporal
organization
process.
Starting
from
alternative
point
view,
recent
work
sheds
light
on
role
an
calcium
release
endoplasmic
reticulum
in
control
nuclear
levels.
is
achieved
through
activation
local
soluble
adenylyl
cyclase
(sAC),
which
turn
regulates
protein
kinase
A
(PKA)
downstream
transcriptional
events.
In
review,
we
explore
dynamic
evolution
research
signaling,
including
findings
that
led
us
formulate
novel
three-wave
hypothesis.
We
delve
into
how
abandoned
generation
membrane
changing
perspectives
rate-limiting
step
PKA
activation.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Oct. 11, 2024
Many
GPCRs
initiate
a
second
phase
of
G
protein-mediated
signaling
from
endosomes,
which
inherently
requires
an
increase
in
protein
activity
on
the
endosome
surface.
