The role of CFTR in facilitating ATP release/signaling remains elusive. Hypotheses were forged that stimulation by cyclic AMP agonists may not be optimal for observing CFTR-facilitated ATP conduction, and that ATP-binding cassette (ABC) transporter-mediated ATP release is important for autocrine and paracrine control of other ionic conductances involved in cell volume control. Autocrine ATP signaling is essential for regulatory volume decrease (RVD) in liver cells. Bioluminescence measurements show that CFTR or mdr augment ATP release under isotonic conditions and potentiate markedly ATP release in response to hypotonicity in wild-type ABC transporter-expressing airway, pancreatic, and liver epithelial cells and in wild-type ABC transporter-expressing fibroblasts when compared to ΔF508-CFTR or null expressing controls. Epithelia expressing wtCFTR also have a heightened sensitivity (5-fold) to dilutions in extracellular osmolality vs. epithelia expressing ΔF508-CFTR. ABC transporter-facilitated and hypotonicity-induced ATP release is inhibited by the mechanosensitive ion channel blocker, gadolinium chloride (GdCl3), and attenuated by osmolar replacement of small anions such as Cl-, I-, and HCO3- (but not by mannitol, sucrose, or gluconate). ATP channels, that are stimulated by pressure gradients, blocked by GdCl3 (50 μM), and not exposed to PKA, are observed in bovine tracheal epithelial vesicle protein preparations immunodepleted of CFTR. wtCFTR accelerates and heightens RVD at least 2-fold when compared to fibroblasts expressing ΔE508-CFTR or lacking CFTR, These results show that CFTR regulates cell volume by facilitating ATP release through a separate yet tightly associated ATP channel upon "sensing" and "transducing" reductions in anionic strength in external milieu as a signal of hypotonicity. ATP would then trigger RVD via autorine signaling through ATP receptors.
|Original language||English (US)|
|State||Published - Mar 20 1998|
ASJC Scopus subject areas
- Molecular Biology