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Rho‐GTP Exchange Factors (GEFs) mediating Ca2+ sensitization in smooth muscle
Author(s) -
Stevenson Andra Samuel,
Korcynska J,
Derewenda U,
Przywara M,
Derewenda Z,
Somlyo A V
Publication year - 2006
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.20.4.a105-a
Subject(s) - rhoa , sensitization , pdz domain , guanine nucleotide exchange factor , microbiology and biotechnology , chemistry , signal transduction , stimulation , biology , immunology , endocrinology
This study examined the role of guanine exchange factors (GEFs) and their specific domains involved in mediating Ca 2+ sensitization. Here, we identify two GEFs, LARG and PDZ‐RhoGEF (PRG) in rabbit pulmonary artery smooth muscle (PA), which have been shown to interact with Gα 12/13 family members via their regulators of G protein signaling (RGS L ) domain. We determined whether these RhoGEFs and which specific domains were involved in Ca 2+ sensitizing actions of U46619, a thromboxane A 2 analogue. U‐46619 was a strong mediator of Ca 2+ sensitization in PA muscle strips. We found that the DH/PH domains of PRG and LARG significantly increased Ca 2+ sensitization (1). The RGS L domains of PRG and LARG, implicated in GEF/RhoA regulation, function as DN inhibitors of this pathway, but surprisingly, no significant effect on U‐46619‐induced sensitization occurred. However, PDZ domains from LARG and PRG caused significant inhibition of U‐46619‐induced sensitization. In control experiments, two PDZ domain fragments of Syntenin, a non‐RhoGEF PDZ domain containing protein showed no inhibition of sensitization. Preliminary studies show co‐localization and interaction of the TP and the PDZ domain of PRG and endogenous PRG in cultured cells. Together, these data suggest that LARG and PRG are involved in signaling via stimulation of GPCR leading to RhoA‐dependent activation of Ca 2+ sensitization in SM. These interactions suggest a mechanistic role for the TP/GEF/RhoA pathway leading to Ca 2+ sensitization in smooth muscle. Supported by NIH P01 HL48807.