Sphingosine-1-Phosphate Is a Novel Regulator of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Activity

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) attenuates sphingosine-1-phosphate (S1P) signaling in resistance arteries and has emerged as a prominent regulator of myogenic vasoconstriction. This investigation demonstrates that S1P inhibits CFTR activity via adenosine monophosphate-activated kinase (AMPK), establishing a potential feedback link. In Baby Hamster Kidney (BHK) cells expressing wild-type human CFTR, S1P (1μmol/L) attenuates forskolin-stimulated, CFTR-dependent iodide efflux. S1P’s inhibitory effect is rapid (within 30 seconds), transient and correlates with CFTR serine residue 737 (S737) phosphorylation. Both S1P receptor antagonism (4μmol/L VPC 23019) and AMPK inhibition (80μmol/L Compound C or AMPK siRNA) attenuate S1P-stimluated (i) AMPK phosphorylation, (ii) CFTR S737 phosphorylation and (iii) CFTR activity inhibition. In BHK cells expressing the ΔF508 CFTR mutant (CFTRΔF508), the most common mutation causing cystic fibrosis, both S1P receptor antagonism and AMPK inhibition enhance CFTR activity, without instigating discernable correction. In summary, we demonstrate that S1P/AMPK signaling transiently attenuates CFTR activity. Since our previous work positions CFTR as a negative S1P signaling regulator, this signaling link may positively reinforce S1P signals. This discovery has clinical ramifications for the treatment of disease states associated with enhanced S1P signaling and/or deficient CFTR activity (e.g. cystic fibrosis, heart failure). S1P receptor/AMPK inhibition could synergistically enhance the efficacy of therapeutic strategies aiming to correct aberrant CFTR trafficking.

Sphingolipids role in the regulation of inflammatory response: From leukocyte biology to bacterial infection

“…1). 59,63 In the context of CF airways pathology, new interest has recently emerged for S1P as regulator of CFTR activity, 64 as well as from the intriguing relationship between altered S1P content and inflammatory response to bacterial infection. 52 The involvement of S1P in CF pathology is supported by evidence that inhibition of S1P degradation is associated with decreased lung inflammatory response to P. aeruginosa in a CF mouse model.…”

The role of sphingosine 1‐phosphate receptor 2 in bile‐acid–induced cholangiocyte proliferation and cholestasis‐induced liver injury in mice

“…(10) S1P and S1PRs have been shown to have differential roles in the regulation of cell proliferation, migration, and survival in different tissues and cells. (11)(12)(13)(14) It has been reported that S1P/S1PR3 signaling is involved in cholestasis-induced liver fibrosis (LF) (15) and S1P mediates bone-marrowderived macrophage migration through activation of S1PR2 and S1PR3 in the bile duct ligation (BDL) mouse model. (16) In addition, antagonism of S1PR2 selectively reduces portal vein pressure in BDL rodents.…”

Comprehensive mapping of cystic fibrosis mutations to CFTR protein identifies mutation clusters and molecular docking predicts corrector binding site

“…In recent years, much effort has been directed toward discovery and development of novel small molecule therapies for CF patients bearing the F508del and G551D mutations, since these mutations capture a large fraction of the patient population. [9][10][11][12][13] Accordingly, 2 small molecule therapies (Kalydeco ® , comprised of the potentiator ivacaftor or VX-770, and Orkambi ® , comprised of ivacaftor and the corrector lumacaftor or VX-809) have been developed for individuals with these mutations (G551D and F508del, respectively), as well as for those having a few other mutations with similar CFTR protein defects. 14,15 However, these discoveries as well as most other investigations typically explore CFTR mutations on a case-by-case basis, and do not consider the global mutation landscape as a whole.…”