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Serine 225 phosphorylation governs the localization and function of sphingosine kinase 1 in resistance arteries
Author(s) -
Lidington Darcy,
Peter Bernhard Friedrich,
Meissner Anja,
Kroetsch Jeff,
Pitson Stuart,
Pohl Ulrich,
Bolz SteffenSebastian
Publication year - 2010
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.24.1_supplement.777.3
Subject(s) - sphingosine 1 phosphate , sphingosine , sphingosine kinase 1 , microbiology and biotechnology , phosphorylation , serine , sphingosine kinase , biology , chemistry , receptor , biochemistry
Sphingosine kinase 1 (Sk1), which synthesizes the vasoconstrictor sphingosine‐1‐phosphate (S1P), must translocate from the cytosol to the plasma membrane in order to access its substrate. We aimed to characterize the serine 225 phosphorylation motif as the molecular switch that regulates the pressure‐dependent activation/translocation of Sk1 in hamster gracilis muscle resistance arteries. Pressure elevation stimulated the phosphorylation of ERK1/2, an upstream activator of Sk1, and the translocation of Sk1 to the plasma membrane. Functionally, preventing Sk1 activation, either by the expression of a non‐phosphorylatable mutant (Sk1 S225A ) or by ERK1/2 inhibition, reduced resting and myogenic tone, resting Ca 2+ , pressure‐induced Ca 2+ elevation and Ca 2+ sensitivity. The effects of Sk1 S225A expression on Ca 2+ were restored by forcing its localization to the plasma membrane, but all other parameters remained inhibited. Forcing wild‐type Sk1 to the plasma membrane inhibited the same parameters. These discrete effects are consistent with cell surface receptor‐mediated effects and intracellular effects of S1P. Accordingly, S1P 2 receptor inhibition attenuated myogenic tone without effect on Ca 2+ . We conclude that: (i) translocation and precise subcellular positioning of Sk1 is essential for full Sk1 function; and (ii) two distinct S1P pools contribute to the maintenance of vascular tone.