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2017 ; 8
(1
): 443
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Internalized TSH receptors en route to the TGN induce local G(s)-protein
signaling and gene transcription
#MMPMID28874659
Godbole A
; Lyga S
; Lohse MJ
; Calebiro D
Nat Commun
2017[Sep]; 8
(1
): 443
PMID28874659
show ga
A new paradigm of G-protein-coupled receptor (GPCR) signaling at intracellular
sites has recently emerged, but the underlying mechanisms and functional
consequences are insufficiently understood. Here, we show that upon
internalization in thyroid cells, endogenous TSH receptors traffic retrogradely
to the trans-Golgi network (TGN) and activate endogenous G(s)-proteins in the
retromer-coated compartment that brings them to the TGN. Receptor internalization
is associated with a late cAMP/protein kinase A (PKA) response at the Golgi/TGN.
Blocking receptor internalization, inhibiting PKA II/interfering with its
Golgi/TGN localization, silencing retromer or disrupting Golgi/TGN organization
all impair efficient TSH-dependent cAMP response element binding protein (CREB)
phosphorylation. These results suggest that retrograde trafficking to the TGN
induces local G(s)-protein activation and cAMP/PKA signaling at a critical
position near the nucleus, which appears required for efficient CREB
phosphorylation and gene transcription. This provides a new mechanism to explain
the functional consequences of GPCR signaling at intracellular sites and reveals
a critical role for the TGN in GPCR signaling.Recent investigations suggest that
G-protein-coupled receptors (GPCRs) can signal during intracellular trafficking.
Here the authors use fluorescence microscopy approaches to directly visualize and
investigate functional consequences of GPCR-mediated signaling at the
Golgi/trans-Golgi network.
|*Signal Transduction
[MESH]
|*Transcription, Genetic
[MESH]
|Animals
[MESH]
|Cells, Cultured
[MESH]
|Cyclic AMP-Dependent Protein Kinases/metabolism
[MESH]
|Endosomes/metabolism
[MESH]
|GTP-Binding Protein alpha Subunits, Gs/*metabolism
[MESH]