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Sphingosine‐1‐Phosphate acutely modulates the CFTR (Cystic Fibrosis Transmembrane Regulator) transporter in an AMPK‐dependent manner
Author(s) -
Malik Firhan Atir,
Meissner Anja,
Bear Christine,
Bolz Steffen Sebastian
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.609.1
Subject(s) - cystic fibrosis transmembrane conductance regulator , ampk , chemistry , sphingosine 1 phosphate , intracellular , sphingosine kinase 1 , sphingosine , sphingosine kinase , phosphorylation , microbiology and biotechnology , protein kinase a , endocrinology , biochemistry , receptor , biology , gene
Sphingosine‐1‐Phosphate (S1P) is a primary modulator of resistance artery tone. Its bioavailability is controlled by a rheostat between sphingosine kinase 1 and intracellular S1P phosphohydrolase 1. We have found that the transport by CFTR is the rate‐limiting step for the intracellular hydrolysis of S1P. We hypothesized that S1P limits its own degradation by an AMPK‐dependent modulation of CFTR conductance. Methods CFTR conductance was assessed using the iodide efflux technique (conventional and real‐time) in baby hamster kidney (BHK) cells, which stably express human wild type CFTR. AMPK phosphorylation was determined using Western blots Results BHK cells were found to endogenously express Sk1, SPP1 and the S1P 1 and S1P 2 receptors (n=8). S1P (1μM, n=6) significantly reduced iodide conductance by 43% (conventional) and 75% (real‐time). The negative effect of S1P on CFTR iodide conductance was enhanced following S1P 2 overexpression but reduced following pretreatment with the S1P 2 blocker JTE013 (5μM, n=6). The inhibitory effect of S1P was associated with AMPK phosphorylation and blocked by the AMPK inhibitor Compound C (80μM, n=5). Accordingly, AMPK activation by AICAR mimicked the effect of S1P on iodide conductance. Conclusions The S1P 2 ‐ and AMPK‐dependent modulation of CFTR conductance describes a novel pathway through which S1P could potentially regulate its own degradation.