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

Abstract

There is indirect evidence that the plasmalemma-integrated eukaryotic porin (the voltage-dependent anion-selective channel, VDAC) functions as the outwardly rectifying chloride channel (ORCC). The channel, which is believed to 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 Gd(3+) altered the voltage dependence of human type-1 porin incorporated into artificial planar lipid bilayers. Next, using a light-scattering approach on transformed normal or CF human B-lymphocytes in hypotonic Ringer solution, we found slightly differing regulatory volume decrease (RVD) curves for the cell lines under study. Addition of 15-60 microM GdCl3 in hypotonic Ringer increased light scattering, pointing 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 Gd(3+)-induced cell swelling was abolished by monoclonal mouse anti-human type-1 porin antibodies. Agonist and antibody effects were dose dependent. Finally, videocamera-monitored control experiments 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 channels, allowing ions to following their gradients, resulting in cell swelling. Since respiratory epithelium expresses porin channels in the apical membrane, the use of gadolinium to activate ORCC may represent a new therapeutic approach in CF.

The Effect of Swelling on TRH and Oxytocin Secretion From Hypothalamic Structures

“…In both osmotic situations, Gd 3+ -induced cell swelling was abolished by monoclonal mouse anti-human type 1 porin antibodies. It was concluded that GdCl 3 opens plasmalemma-integrated porin channels and thus allows ions to follow their gradients resulting in cell swelling (Thinnes et al, 2001). Therefore, it is likely that GdCl 3 in our experiments obviated a specific response to osmolarity changes and thus unmasked general nonspecific cellular response to hypotonicity.…”

“…Magnocellular neurons in the SON increase cell size in response to hyperosmolar conditions and decrease cell size in response to hyposmolar conditions (Zhang et al, 2001). Thinnes et al (2001) using a light-scattering approach on transformed normal or CF human B-lymphocytes in hypotonic Ringer solution found that the addition of 15-60 µM GdCl 3 increased cell swelling beyond normal values. Regulatory volume decrease (RVD) was not observed in those experiments.…”

Gadolinium Chloride Restores the Function of the Gap Junctional Intercellular Communication between Hepatocytes in a Liver Injury

“…In our study, we also examined the effects of Mg 2+ and Ca 2+ upon the expression of connexin proteins in CCl 4 - or LPS-treated hepatocytes, showing that MgCl 2 or CaCl 2 had no influence on the mRNA expression of Cx32 and Cx26. Moreover, several studies suggest that gadolinium serves as an alleviator of P450 induction [42] and an opener of plasma-integrated porin channels [43]. Further studies will be needed to assess the exact mechanism underlying the regulation of GJIC function and the expression of Cx32 and Cx26 by GdCl 3 in our models.…”

Cell volume regulation: osmolytes, osmolyte transport, and signal transduction

“…Based on the effects of cytochalasins, a direct regulatory interaction with the actin cytoskeleton is assumed Nilius et al 1997). BCl channels may be related to the voltage-dependent anion channel (VDAC), a porin-like channel found in eukaryotic mitochondria or to the brain-derived voltage-dependent anion channel 1 (BR1-VDAC), which is also expressed in lymphocytes, kidney, heart, and skeletal muscle (Dermietzel et al 1994;Thinnes et al 2001).…”