the role of HSP90 in the 2C AR
intracellular traffic regulation. The
folding of the newly synthesized proteins
and the subcellular transport is assisted
by many specialized proteins, broadly
named molecular
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classes and intervene at different steps
during protein maturation or trafficking,
modulating the transport rate and the
subcellular localization. In the case of
misfolded proteins it has been repeatedly
demonstrated that several molecular
chaperones, actively prevent formation of
aggregates by triggering the unfolded
protein response. In particular, HSP90 has
been shown to modulate the folding,
stabilization, activation, and assembly of
a wide range of proteins.
Still,
in contrast with other molecular
chaperones, HSP90 has a distinct
repertoire of specific,client, proteins
with which
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the role of scaffold and regulating the
maturation and signaling of these
molecules. Alterations in the HSP90
activity have been demonstrated to modify
the intracellular trafficking and plasma
membrane targeting of different mutants of
CFTR, insulin receptor and nicotinic
receptor. Thus far, just one another GPCR
member, the cannabinoid CB2 receptor has
been reported to interact with HSP90 and
this interaction is required for the
receptor mediated cell migration through
the Gi Rac1 pathway.
However, no
attempt to quantify the HSP90 effects on
the receptor subcellular localization and
plasma membrane expression was performed
in the respective study. href="">
The
the 2C AR traffic to the plasma membrane
was demonstrated in the present study by
two separate and complimentary means,
inhibition of its activity using specific
inhibitors and decreasing the cellular
Similar results were obtained with
both approaches, demonstrating that HSP90
activity is essential for the receptor
accumulation at the physiological
temperature. Again, wild type 2C AR and
2C322 325del AR polymorphic variant have
similar sensitivity, clearly showing that
both isoforms have similar trafficking
properties at least in respect to the
effects of low temperature and HSP90
modulation.
Because no changes were
observed in the total receptor levels at
the two temperatures, and the specific
proteasomal inhibitors MG132 and
lactacystin have no effects on the 2C AR
trafficking, it can be concluded that low
temperature acts by releasing the
inhibitory mechanisms preventing the
receptor transport at physiological
temperature.
Based on the absence of
HSP90 inhibitors at 30, it can be assumed
that these mechanisms are at least in part
mediated by HSP90. HSP90 has multiple
isoforms with different subcellular
localization and different functions. The
current HSP90 inhibitors are a little more
effective against the cytosolic isoforms.
Indeed, overexpression of GRP94, the
endoplasmic reticulum HSP90 isoform, had
no effect on the 2C AR trafficking. This
finding is not surprising, considering
that in contrast to other endoplasmic
reticulum resident molecular chaperones,
GRP94 has been suggested to have a limited
number of interacting partners. The
correlation between the data obtained with
three distinct HSP90 inhibitors and
specific down regulation of cytosolic
HSP90 levels using