Gadolinium as an opener of the outwardly rectifying Cl- channel (ORCC). Isthere relevance for cystic fibrosis therapy?

There is indirect evidence that the plasmalemma-integrated eukaryotic porin (the voltage-dependent anion-selective channel, VDAC) functions as the out wardly rectifying chloride channel (ORCC). The channel, which is believed t o play a role in cell volume regulation, appears to be relevant for cystic fibrosis (CF) therapy, in that it may function as an alternative Cl-channel . In the present study we showed first that Gd3+ altered the voltage depend ence of human type-1 porin incorporated into artificial planar lipid bilaye rs. Next, using a light-scattering approach on transformed normal or CF hum an B-lymphocytes in hypotonic Ringer solution, we found slightly differing regulatory volume decrease (RVD) curves for the cell lines under study. Add ition of 15-60 muM GdCl3 in hypotonic Ringer increased light scattering, po inting to cell swelling beyond normal values. RVD was not observed in those experiments. A corresponding effect was seen in isotonic Ringer containing GdCl3, In either osmotic situation Gd3+-induced cell swelling was abolishe d by monoclonal mouse antihuman type-1 porin antibodies. Agonist and antibo dy effects were dose dependent. Finally, videocamera-monitored control expe riments with adherent HeLa cells verified the direct effect of the agonist on cell swelling in hypo- or isotonic situations and its prevention by the antibodies. We conclude that GdCl3 opens plasmalemma-integrated porin chann els, allowing ions to following their gradients, resulting in cell swelling . Since respiratory epithelium expresses porin channels in the apical membr ane, the use of gadolinium to activate ORCC may represent a new therapeutic approach in CF.