Failure of the Cystic Fibrosis Transmembrane Conductance Regulator to Conduct ATP

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride ion channel regulated by protein kinase A and adenosine triphosphate (ATP). Loss of CFTR-mediated chloride ion conductance from the apical plasma membrane of epithelial cells is a primary physiological lesion in cystic fibrosis. CFTR has also been suggested to function an an ATP channel, although the size of the ATP anion is much larger than the estimated size of the CFTR pore. ATP was not conducted through CFTR in intact organs, polarized human lung cell lines, stably transfected mammalian cell lines, or planar lipid bilayers reconstituted with CFTR protein. These findings suggest that ATP permeation through the CFTR is unlikely to contribute to the normal function of CFTR or to the pathogenesis of cystic fibrosis.

Bacterial RTX Toxins Allow Acute ATP Release from Human Erythrocytes Directly through the Toxin Pore

“…Regarding CFTR, this channel was initially suggested as an important ATP release channel. According to recent literature, however, it seems that CFTR in itself is not the ATP release channel but, instead, this transporter is involved in regulatory mechanisms leading to ATP release through other exit pathways (17)(18)(19)(20)(21). Our previous data has, however, left limited, if any, room for CFTR in the HlyA-induced hemolysis as we found similar HlyA-induced lysis in erythrocytes isolated from CFTR wild type and knock-out mice (26).…”

“…CFTR has been suggested to be necessary for ATP release upon mechanical deformation (10) as well as low O 2 and prostacyclin stimulation (16). It is, however, now recognized that CFTR is more likely to regulate other channels and not being directly involved in ATP release itself (17)(18)(19)(20)(21). In line with this, a recent study showed that CFTR is involved in ATP release induced by both low O 2 and prostacyclin stimulation but the exit pathway appeared to be pannexin 1 in the case of low O 2 tension (16) and VDAC for prostacyclinmediated ATP release (14).…”

ATP release from non-excitable cells

“…However, a significant number of studies failed to detect differences in extracellular ATP in normal and CFTR-deficient epithelial tissues [78][79][80]. It was also shown that swelling-induced ATP release was independent from CFTR [32,46,81].…”

Vesicular and conductive mechanisms of nucleotide release

“…The multidrug resistance (MDR)-1 protein, the CF transmembrane conductance regulator (CFTR) Cl − channel, and the mitochondrial voltage-dependent anion channel-1 (VDAC-1) were initially proposed as ATP release pathways or facilitators of ATP release in various cell types, but the involvement of these proteins in an ATP release function could not be corroborated by a number of studies [90][91][92][93][94][95][96]; for a critical review on these proposed pathways, see [8,97]. More recently, two classes of plasma membrane channels have been associated with an ATP conductive activity: (1) Cl − channels such as maxi anion channels, volume-regulated ion channels, and tweety; and (2) pore forming connexins, pannexins, and P2X7 receptors.…”