title: Serotonin improves glucose metabolism by Serotonylation of the small GTPase Rab4 in L6 skeletal muscle cells.
abstract: BACKGROUND
  Serotonin (5-HT) improves insulin sensitivity and glucose metabolism, however, the underlying molecular mechanism has remained elusive. Previous studies suggest that 5-HT can activate intracellular small GTPases directly by covalent binding, a process termed serotonylation. Activated small GTPases have been associated with increased GLUT4 translocation to the cell membrane. Therefore, we investigated whether serotonylation of small GTPases may be involved in improving Insulin sensitivity and glucose metabolism.
  
  
  METHODS
  Using fully differentiated L6 rat skeletal muscle cells, we studied the effect of 5-HT in the absence or presence of insulin on glycogen synthesis, glucose uptake and GLUT4 translocation. To prove our L6 model we additionally performed preliminary experiments in C2C12 murine skeletal muscle cells.
  
  
  RESULTS
  Incubation with 5-HT led to an increase in deoxyglucose uptake in a concentration-dependent fashion. Accordingly, GLUT4 translocation to the cell membrane and glycogen content were increased. These effects of 5-HT on Glucose metabolism could be augmented by co-incubation with insulin and blunted by co incubation of 5-HT with monodansylcadaverine, an inhibitor of protein serotonylation. In accordance with this observation, incubation with 5-HT resulted in serotonylation of a protein with a molecular weight of approximately 25 kDa. We identified this protein as the small GTPase Rab4, the activity of which has been shown to be stimulated by both insulin signalling and serotonylation.
  
  
  CONCLUSIONS
  Our data suggest that 5-HT elicits its beneficial effects on Glucose metabolism through serotonylation of Rab4, which likely represents the converging point between the insulin and the 5-HT signalling cascades.
authors.affiliation: Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Ramona
authors.identifier: 0000-0001-6450-2630
authors.initials: R
authors.lastname: Al-Zoairy
authors.affiliation: Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Pedrini
authors.affiliation: Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Mohammad Imran
authors.initials: MI
authors.lastname: Khan
authors.affiliation: Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Engl
authors.affiliation: Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Tschoner
authors.affiliation: Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Ebenbichler
authors.affiliation: Section of Physiology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gstraunthaler
authors.affiliation: Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Salzmann
authors.affiliation: Institute of Analytical Chemistry and Radiochemistry, Leopold-Franzens University Innsbruck, Innsbruck, Austria.
authors.forename: Rania
authors.initials: R
authors.lastname: Bakry
authors.affiliation: Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Niederwanger
keywords: GLUT4; Glucose uptake; L6 skeletal muscle cells; Rab4; Serotonin; Serotonylation