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Cyclic AMP‐Rap1A signaling mediates cell surface translocation of microvascular smooth muscle α 2C adrenoceptors through the actin binding protein filamin‐2
Author(s) -
Motawea Hanaa KB,
Jeyaraj Selvi C,
Pawlowski Marcin,
Kloczkowski Andrzej,
Chotani Maqsood A.
Publication year - 2013
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.27.1_supplement.729.15
Subject(s) - filamin , microbiology and biotechnology , vascular smooth muscle , actin , phosphorylation , signal transduction , rhoa , heterotrimeric g protein , receptor , biology , chemistry , g protein , biochemistry , cytoskeleton , cell , endocrinology , smooth muscle
The second messenger cyclic AMP (cAMP) plays a vital role in vascular physiology, including vasodilation of large blood vessels. We recently demonstrated cAMP activation of Epac‐Rap1A and RhoA‐ROCK‐F‐actin signaling in arteriolar smooth muscle cells to increase expression and cell surface translocation of functional α 2C adrenoceptors (α 2C ‐ARs) that mediate vasoconstriction. This study examined the mechanism of translocation to better understand the role of these newly discovered mediators of blood flow control, potentially activated in peripheral vascular disorders. We have identified a novel protein‐protein association between α 2C ‐AR C‐terminus 14 amino acids and the actin‐binding protein filamin‐2, which was confirmed by site‐directed mutagenesis and co‐immunoprecipitation, co‐localization, and siRNA knock‐down approaches. Computational modeling and docking predictions further supported the specificity of this interaction. The cAMP‐Rap1‐ Rho‐ROCK signaling facilitated receptor translocation via phosphorylation of filamin‐2 Ser‐2113. The α 2C ‐AR 14 amino acids region, when used as decoy peptide, inhibited endogenous receptor surface translocation. Together, these studies show a vital role of the C‐terminus in receptor translocation, and provide a rationale for designing protein‐protein interaction small molecule inhibitor as a novel approach to target intracellular α 2C ‐ARs.