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RGS protein regulation and signaling diversity of protease‐activated receptors (PAR1 and PAR2)
Author(s) -
McCoy Kelly L.,
Waters Jon P.,
Hepler John R.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.907.4
Subject(s) - rgs2 , g protein , g protein coupled receptor , microbiology and biotechnology , gtpase activating protein , regulator of g protein signaling , signal transduction , gq alpha subunit , heterotrimeric g protein , receptor , biology , scaffold protein , gtp binding protein regulators , g beta gamma complex , biochemistry
PAR signaling must be tightly controlled since these G protein coupled receptors are proteolytically cleaved and thereby irreversibly activated. R egulators of G protein s ignaling (RGS) proteins provide a potential mechanism for such regulation since their conserved RGS domains give them the capacity to act as GTPase‐activating proteins and thereby inhibit G protein signaling. Little is known about RGS regulation of PAR signaling but our data using purified proteins and intact cells suggest that RGS2 and RGS4 but not RGS1 or RGS16, directly bind to and selectively regulate PAR1 and PAR2 signaling. Adding to the complexity of these studies, PAR1 and PAR2 have both been shown to couple to Gi, Gq, and G12. Our data shows that PAR1 and PAR2 activation of Gq (and potentially other G proteins) can be blocked by RGS2 and RGS4 but not by RGS1 or RGS16. Using selective G protein inhibitors and receptor mutants, ongoing studies will determine whether RGS regulation of PARs is receptor‐dependent, G protein‐ dependent or both. A detailed understanding of PAR signaling will provide insight into how these promiscuous receptors activate multiple G proteins and how their divergent signaling pathways are regulated. These studies will define PAR signaling mechanisms that underlie their roles in cellular processes such as inflammation, gliosis, and hyperalgesia. Support: R01NS037112 and R01NS049195 (JRH), A.H.A. 0715465B (KLM).