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caveolin-1 in a Src-dependent manner. Phosphocaveolin-1 then binds to the SH2
domain of the C-terminal Src kinase (Csk) resulting in a rapid decrease in Src kinase
activity. Thus, PAR1-induced Src activation is down-regulated by recruiting Csk
specifically in caveolin-1 containing microdomains (Lu et al.
2006
) .
GnRH receptors have been shown to constitutively localize within microdomains
as part of a preformed signaling complex composed of caveolin-1, c-Src, protein
kinase C, Ras, MAPK kinase 1/2, ERK1/2, tubulin, FAK, paxillin, vinculin, and
kinase suppressor of Ras-1 (Dobkin-Bekman et al.
2009
) . Stimulation by GnRH
induces molecular rearrangement of the complex, the rapid dissociation of some
components and the phosphorylation of FAK and paxillin by EKR1/2. Whereas acti-
vation of ERK1/2 typically induces their nuclear translocation and phosphorylation
of transcription factors, scaffolding into microdomain-associated multiprotein sig-
naling complexes, as described here, helps to maintain the activated ERK1/2 pool
within the cytoplasm and to phosphorylate FAK and paxillin at focal adhesions.
Primary cilia are appendages present at the cell surface on most mammalian cells
involved in signal sensing and transmission (Goetz and Anderson
2010
) . Some
GPCRs, including somatostatin receptor 3, serotonin receptor 6, smoothened,
dopamine D
1
receptor and melanin-concentrating hormone receptor 1 localize to cilia.
The importance of the localization and signaling of GPCRs in primary cilia is sug-
gested by altered signaling caused by the absence of cilia formation (Berbari et al.
2009
). Some molecular determinants directing localization of GPCRs to cilia have
been identified in the third intracellular loop, which most likely binds to cytoskeleton
proteins involved in the transport into and out of cilia (Berbari et al.
2008
) . The func-
tions of cilia are defined by the signaling proteins localized to the ciliary membrane
such as adenylyl cyclases, heterotrimeric G proteins and ß-arrestins. What makes
primary cilia so special compared to other cell surface-exposed membrane regions,
remains still an open question and warrants further investigation.
Many GPCRs contain a PSD-95/Disc large/Zonula occludens 1 (PDZ) ligand
sequence composed of three amino acids at their carboxyl-terminal extremity
(Heydorn et al.
2004
). These PDZ ligands are recognized by PDZ domains, which
are present in almost 200 proteins. PDZ domains are scaffolding domains per excel-
lence that are involved in GPCR trafficking and subcellular localization. The post-
synaptic density protein 95 (PSD95) contains three PDZ domains and interacts with
the serotonin 5-HT
2C
receptor and other GPCRs in post-synaptic membranes
(Becamel et al.
2002
). PSD95 is also part of large molecular networks such as the
PSD95/GKAP/Shank/Homer3 complex that physically and functionally connects
NMDA receptors (PSD95 binding partner) to metabotropic glutamate 5 receptors
(mGluR5) (Homayoun and Moghaddam
2010
). Homer three proteins assemble into
tetramers bridging GKAP and mGluR5. Interestingly, this complex can be disrupted
by the monomeric immediate early gene Homer1a that blocks the interaction
between GKAP and mGluR5 by competing with Homer3. This indicates a dynamic
regulation of the presence of mGluR5 in the complex and possibly its localization
to post-synaptic membranes (Bertaso et al.
2010
) .
Signaling of GPCRs has been reported not only at the plasma membrane or
specialized plasma membrane sub-compartments such as microdomains, primary
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