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Pharmacochaperone-mediated rescue of calcium-sensing receptor loss-of-function mutants.
[familial hypocalciuric hypercalcemia]
The
calcium
sensing
receptor
(
CaSR
)
is
a
Family
C
/
3
G
protein-coupled
receptor
that
translates
changes
in
extracellular
Ca
(
2
+
)
into
diverse
intracellular
signals
.
Loss
-of-function
mutations
in
human
CaSR
cause
familial
hypocalciuric
hypercalcemia
and
neonatal
severe
hyperparathyroidism
.
CaSR
must
navigate
a
number
of
endoplasmic
reticulum
quality
control
checkpoints
during
biosynthesis
,
including
a
conformational
/
functional
checkpoint
.
Here
we
examine
the
biosynthesis
of
25
CaSR
mutations
causing
familial
hypocalciuric
hypercalcemia
/
neonatal
severe
hyperparathyroidism
using
immunoprecipitation
,
biotinylation
,
and
functional
assays
.
We
define
classes
of
CaSR
mutants
based
on
their
biosynthetic
profile
.
Class
I
CaSR
mutants
are
not
rescued
to
the
plasma
membrane
.
To
dissect
the
organellar
compartments
that
class
I
mutants
can
access
,
we
engineered
a
cleavage
site
for
the
proprotein
convertase
furin
into
the
extracellular
domain
of
wild-
type
CaSR
and
class
I
mutants
.
Based
on
absence
or
presence
of
cleavage
fragments
,
we
find
most
mutants
are
degraded
from
the
endoplasmic
reticulum
(
no
furin-mediated
cleavage
)
,
whereas
others
access
the
Golgi
(
furin-mediated
cleavage
)
before
degradation
.
Class
II
CaSR
mutants
show
increased
expression
and
/
or
enhanced
plasma
membrane
localization
upon
treatment
with
MG
132
or
the
pharmacochaperone
NPS
R-
568
,
permitting
assay
of
functional
activity
.
Of
the
10
CaSR
mutants
that
exhibit
plasma
membrane
localization
,
only
two
did
not
show
enhanced
functional
activity
after
rescue
with
NPS
R-
568
.
The
established
approaches
can
be
used
with
current
and
newly
identified
CaSR
mutations
to
identify
the
location
of
biosynthetic
block
and
to
determine
the
likelihood
of
rescue
by
allosteric
agonists
.
Diseases
Validation
Diseases presenting
"functional checkpoint"
symptom
familial hypocalciuric hypercalcemia
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