title: Melatonin down-regulates volume-sensitive chloride channels in fibroblasts.
abstract: Melatonin has been reported to present with vasorelaxant and anti-fibrotic properties. We hypothesized that melatonin may down-regulate volume-regulated anion channels (VRAC) in fibroblasts to limit their migration and proliferation. While acute exposure of L929 fibroblasts to melatonin did not result in a significant decrease in VRAC current, pretreatment with 100 μM melatonin for 1 h decreased swelling-dependent activation of anion currents by 83% as measured by whole-cell perforated patch-clamp technique. This down-regulation of VRAC currents was dose-dependent with a half-maximal inhibition of 3.02 ± 0.48 μM. Overnight treatment of cells with 100 nM melatonin had the same inhibitory potency as a 1-h treatment with 100 μM. A similar down-regulatory effect of melatonin on VRAC was observed in primary rat lung fibroblasts. The effect of melatonin was prevented by luzindole and K185 that suggests implication of MT2 receptor. GF109203X, a protein kinase C inhibitor, blocked melatonin's action on VRAC, indicating that MT2 receptor activation results in stimulation of PKC. Consequently, melatonin inhibited regulatory volume decrease following hypotonic swelling of cells. Melatonin also decreased the migration of L929 fibroblasts through the same pathways that blocked VRAC. There was no significant inhibition of cell proliferation. Our study suggests that the attenuation of fibrosis and vascular remodeling by melatonin seen in animal models of hypertension and pulmonary fibrosis might be, in part, related to blunted fibroblast migration possibly through protein kinase C-mediated decrease in chloride channel activity.
authors: Department of Physiology, Université Libre de Bruxelles, Route de Lennik 808, CP604, 1070, Brussels, Belgium.
authors: Ismail
authors: I
authors: Ben Soussia
authors: Frédérique
authors: F
authors: Mies
authors: Robert
authors: R
authors: Naeije
authors: Vadim
authors: V
authors: Shlyonsky
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D048429:Cell Size; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008550:Melatonin / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D044123:Receptor, Melatonin, MT2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014363:Tryptamines / Q000494:pharmacology
chemical_list: D018118:Chloride Channels; D007211:Indoles; C121418:K 185; D008301:Maleimides; D044123:Receptor, Melatonin, MT2; D014363:Tryptamines; C057154:luzindole; D011493:Protein Kinase C; D008550:Melatonin; C070515:bisindolylmaleimide I