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.
Highlights
Sphingosine-1-phosphate (S1P) is a key endogenous regulator of resistance artery myogenic vasoconstriction [1,2,3]
To finely tune S1P signaling, a robust degradation mechanism counterbalances endogenous S1P production. This mechanism depends on two key elements: first, the cystic fibrosis transmembrane conductance regulator (CFTR) transports extracellular S1P across the plasma membrane, thereby sequestering it from its receptors; the internalized S1P is degraded by the intracellular S1P phosphohydrolase 1 (SPP1) [5,6]
Of the CFTR/SPP1 pair, CFTR is ideally positioned to partner the dynamic modulation of S1P degradation with S1P synthesis, since it functions as the primary bottleneck governing S1P degradation in VSMCs [5,6]
Summary
Sphingosine-1-phosphate (S1P) is a key endogenous regulator of resistance artery myogenic vasoconstriction [1,2,3]. Pressure elevation stimulates sphingosine kinase 1 (Sphk1) and S1P production in microvascular smooth muscle cells (VSMCs) [2], which subsequently activates an array of pro-constrictive signaling cascades [4]. To finely tune S1P signaling, a robust degradation mechanism counterbalances endogenous S1P production. This mechanism depends on two key elements: first, the cystic fibrosis transmembrane conductance regulator (CFTR) transports extracellular S1P across the plasma membrane, thereby sequestering it from its receptors; the internalized S1P is degraded by the intracellular S1P phosphohydrolase 1 (SPP1) [5,6]. Our previous work in resistance arteries has characterized Sphk and CFTR/SPP1 as the principal counteracting signaling elements within a signaling framework that precisely controls S1P bioavailability and its pro-constrictive actions. We propose that adenosine monophosphate-activated protein kinase (AMPK), both a S1P signaling target [7,8] and a negative CFTR regulator [9,10], serves as the critical intermediary
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