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Melatonin down-regulates volume-sensitive chloride channels in fibroblasts
Ismail Ben Soussia1, Frédérique Mies, Robert Naeije
1Department of Physiology, Université Libre de Bruxelles, Route de Lennik 808, CP604, 1070, Brussels, Belgium.
Pflugers Archiv : European Journal of Physiology
|July 28, 2012
Summary
Melatonin down-regulates volume-regulated anion channels (VRAC) in fibroblasts, reducing their migration. This effect, mediated by the MT2 receptor and protein kinase C, may explain melatonin
Area of Science:
- Cell Biology
- Pharmacology
- Physiology
Background:
- Melatonin exhibits vasorelaxant and anti-fibrotic properties.
- Volume-regulated anion channels (VRAC) are implicated in fibroblast migration and proliferation.
Purpose of the Study:
- To investigate the hypothesis that melatonin down-regulates VRAC in fibroblasts.
- To elucidate the role of VRAC in melatonin's anti-fibrotic effects.
Main Methods:
- Whole-cell perforated patch-clamp technique to measure VRAC currents in L929 and primary rat lung fibroblasts.
- Dose-response and time-course experiments with melatonin.
- Pharmacological inhibition using luzindole, K185, and GF109203X.
- Assays for cell migration and proliferation.
Main Results:
- Melatonin pretreatment significantly decreased swelling-dependent VRAC currents in a dose-dependent manner (IC50 ≈ 3 μM).
- The effect was mediated by the MT2 receptor and protein kinase C (PKC) activation.
- Melatonin inhibited regulatory volume decrease and fibroblast migration but not proliferation.
Conclusions:
- Melatonin attenuates fibroblast migration by down-regulating VRAC activity via the MT2 receptor-PKC pathway.
- This mechanism likely contributes to melatonin's observed anti-fibrotic and anti-vascular remodeling effects in vivo.
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