Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 29, Issue 11, Pages 1916-U494Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.109.194803
Keywords
myogenic vasoconstriction; signal transduction; transfection; ERK1/2; sphingosine-1-phosphate
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Funding
- Canadian Institutes of Health Research Fellowship [63761]
- European Union Exgenesis [LSHM-CT-2004-005272]
- University of Toronto
- Heart and Stroke Foundation of Ontario [NA6198]
- Canadian Foundation for Innovation
- Ontario Research Fund [11810]
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Objective-The purpose of this study was to characterize a phosphorylation motif at serine 225 as a molecular switch that regulates the pressure-dependent activation of sphingosine kinase 1 (Sk1) in resistance artery smooth muscle cells. Methods and Results-In isolated hamster gracilis muscle resistance arteries, pressure-dependent activation/translocation of Sk1 by ERK1/2 was critically dependent on its serine 225 phosphorylation site. Specifically, expression of Sk1(S225A) reduced resting and myogenic tone, resting Ca2+, pressure-induced Ca2+ elevations, and Ca2+ sensitivity. The lack of function of the Sk1(S225A) mutant could not be entirely overcome by forced localization to the plasma membrane via a myristoylation/palmitylation motif; the membrane anchor also significantly inhibited the function of the wild-type Sk1 enzyme. In both cases, Ca2+ sensitivity and myogenic tone were attenuated, whereas Ca2+ handling was normalized/enhanced. These discrete effects are consistent with cell surface receptor-mediated effects (Ca2+ sensitivity) and intracellular effects of S1P (Ca2+ handling). Accordingly, S1P(2) receptor inhibition (1 mu mol/L JTE013) attenuated myogenic tone without effect on Ca2+. Conclusions-Translocation and precise subcellular positioning of Sk1 is essential for full Sk1 function; and two distinct S1P pools, proposed to be intra- and extracellular, contribute to the maintenance of vascular tone. (Arterioscler Thromb Vasc Biol. 2009; 29:1916-1922.)
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