Regulation of Cl- channels in normal and cystic fibrosis airway epithelial cells by extracellular ATP.

Abstract

The rate of Cl- secretion by human airway epithelium is determined, in part, by apical cell membrane Cl- conductance. In cystic fibrosis airway epithelia, defective regulation of Cl- conductance decreases the capability to secrete Cl-. Here we report that extracytosolic ATP in the luminal bath of cultured human airway epithelia increased transepithelial Cl- secretion and apical membrane Cl- permeability. Single-channel studies in excised membrane patches revealed that ATP increased the open probability of outward rectifying Cl- channels. The latter effect occurs through a receptor mechanism that requires no identified soluble second messengers and is insensitive to probes of G protein function. These results demonstrate a mode of regulation of anion channels by binding ATP at the extracellular surface. Regulation of Cl- conductance by external ATP is preserved in cystic fibrosis airway epithelia.

An electrophysiological study of excitatory purinergic neuromuscular transmission in longitudinal smooth muscle of chicken anterior mesenteric artery

“…Data presented in this study showed that ATP (adenine nucleotide) and UTP (uridine nucleotide) produced approximately equal membrane depolarization upon their exogenous application, indicating the expression of P2Y 2 receptors on the longitudinal smooth muscle of chicken anterior mesenteric artery. Secondary to activation of PLC and mobilization of Ca 2 þ , the P2Y 2 -like receptor mediates the opening of Ca 2 þ -sensitive Cl À channels in airway epithelia Stutts et al, 1992) and avian exocrine salt gland cells (Martin & Shuttleworth, 1995). Similarly, our data showed that the Cl À channel blocker NPPB significantly inhibited the EFS-evoked depolarization as well as the exogenous application of ATP and 2-MeSATP.…”

Agonist-induced phosphorylation and desensitization of the P2Y2 nucleotide receptor

“…Nucleotides acting through the P2Y 2 receptor have been shown to induce Cl − secretion in airway epithelial cells that is not dependent on the cystic fibrosis transmembrane-conductance regulator (5), and P2Y 2 receptor ligands have been proposed as novel class of medication for treatment of retinal detachment (6) and improved mucociliary clearance in clinical conditions such as cystic fibrosis (7).…”

Calcium- and CaMKII-dependent chloride secretion induced by the microsomal Ca(2+)-ATPase inhibitor 2,5-di-(tert-butyl)-1,4-hydroquinone in cystic fibrosis pancreatic epithelial cells.

“…Pharmacological strategies aimed at conquering the CF defect in Cl-secretion have in recent years focused on discovering new agents that would stimulate epithelial Cl -secretion through an alternate cAMP-independent mechanism (for review see reference 4). A number of purinoceptor agonists have recently been shown to enhance Cl-secretion in CF epithelial cells (5)(6)(7)(8). P2 purinoceptor agonists ATP and UTP, in particular, have been tested in clinical trails (9).…”