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Biased signaling through G-protein-coupled PROKR2 receptors harboring missense mutations.
[kallmann syndrome]
Various
missense
mutations
in
the
gene
coding
for
prokineticin
receptor
2
(
PROKR
2
)
,
a
G-
protein-coupled
receptor
,
have
been
identified
in
patients
with
Kallmann
syndrome
.
However
,
the
functional
consequences
of
these
mutations
on
the
different
signaling
pathways
of
this
receptor
have
not
been
studied
.
We
first
showed
that
the
wild-
type
PROKR
2
can
activate
different
G-
protein
subtypes
(
Gq
,
Gs
,
and
Gi
/
o
)
and
recruit
β-arrestins
in
transfected
HEK-
293
cells
.
We
then
examined
,
for
each
of
these
signaling
pathways
,
the
effects
of
9
mutations
that
did
not
significantly
impair
cell
surface
targeting
or
ligand
binding
of
the
receptor
.
Four
mutant
receptors
showing
defective
Gq
signaling
(
R
85
C
,
R
85
H
,
R
164
Q
,
and
V
331
M
)
could
still
recruit
β-arrestins
on
ligand
activation
,
which
may
cause
biased
signaling
in
vivo
.
Conversely
,
the
R
80
C
receptor
could
activate
the
3
types
of
G
proteins
but
could
not
recruit
β-arrestins
.
Finally
,
the
R
268
C
receptor
could
recruit
β-arrestins
and
activate
the
Gq
and
Gs
signaling
pathways
but
could
not
activate
the
Gi
/
o
signaling
pathway
.
Our
results
validate
the
concept
that
mutations
in
the
genes
encoding
membrane
receptors
can
bias
downstream
signaling
in
various
ways
,
possibly
leading
to
pathogenic
and
,
perhaps
in
some
cases
,
protective
(
e
.
g
.
,
R
268
C
)
effects
.
Diseases
Validation
Diseases presenting
"pathogenic"
symptom
kallmann syndrome
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