The phosphorylation motif at serine 225 governs the localization and function of sphingosine kinase 1 in resistance arteries.
Arterioscler Thromb Vasc Biol
; 29(11): 1916-22, 2009 Nov.
Article
em En
| MEDLINE
| ID: mdl-19729605
ABSTRACT
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 ANDRESULTS:
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 Ca(2+), pressure-induced Ca(2+) elevations, and Ca(2+) 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, Ca(2+) sensitivity and myogenic tone were attenuated, whereas Ca(2+) handling was normalized/enhanced. These discrete effects are consistent with cell surface receptor-mediated effects (Ca(2+) sensitivity) and intracellular effects of S1P (Ca(2+) handling). Accordingly, S1P(2) receptor inhibition (1 micromol/L JTE013) attenuated myogenic tone without effect on Ca(2+).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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Artérias
/
Serina
/
Resistência Vascular
/
Fosfotransferases (Aceptor do Grupo Álcool)
/
Músculo Liso Vascular
Limite:
Animals
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article