Serotonin decreases cytoskeletal and cytosolic glycolytic enzymes and the levels of ATP and glucose 1,6-bisphosphate in skin, which is prevented by the calmodulin antagonists thioridazine and clotrimazole.
Serotonin (5-hydroxytryptamine) is believed to play a pathogenic role in skin damage and various skin abnormalities; however, its mechanism of action remains unknown. We show here that intradermal injection of serotonin in rats induced a marked reduction in the activities of the glycolytic enzymes, phosphofructokinase (EC 2.7.1.11) and aldolase (EC 4.1.2.13), in both the cytoskeletal and cytosolic fractions from skin. Serotonin also decreased the levels of glucose 1,6-bisphosphate in skin, the powerful regulator of glucose metabolism. These serotonin-induced changes were accompanied by a marked decrease in ATP content in skin. All these pathological changes induced by serotonin were prevented by treatment with two structurally different calmodulin antagonists: thioridazine, an antipsychotic phenothiazine, or clotrimazole, from the group of the antifungal azole derivatives that were recently recognized as calmodulin antagonists. The present results suggest that calmodulin antagonists may be effective drugs in the treatment of skin damage under various pathological conditions and diseases in which serotonin levels are increased.
Ashkenazy-Shahar
M
M
Department of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
Beitner
R
R
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D003022:Clotrimazole / Q000494:pharmacology; D003599:Cytoskeleton / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005634:Fructose-Bisphosphate Aldolase / Q000037:antagonists & inhibitors; D019298:Glucose-6-Phosphate / Q000031:analogs & derivatives* / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D007700:Kinetics; D010732:Phosphofructokinase-1 / Q000037:antagonists & inhibitors; D051381:Rats; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism*; D013881:Thioridazine / Q000494:pharmacology
D002147:Calmodulin; D012701:Serotonin; D019298:Glucose-6-Phosphate; D000255:Adenosine Triphosphate; C016473:glucose-1,6-bisphosphate; D010732:Phosphofructokinase-1; D005634:Fructose-Bisphosphate Aldolase; D003022:Clotrimazole; D013881:Thioridazine