title: Serotonin stimulates mouse skeletal muscle 6-phosphofructo-1-kinase through tyrosine-phosphorylation of the enzyme altering its intracellular localization.
abstract: Serotonin (5-HT) is a hormone implicated in the regulation of many physiological and pathological events. One of its most intriguing properties is the ability to up-regulate mitosis. Moreover, it has been shown that 5-HT stimulate glucose uptake on skeletal muscle, suggesting that 5-HT may regulate glucose metabolism of peripheric tissues. Here we demonstrate that 5-HT stimulates skeletal muscle 6-phosphofructo-1-kinase (PFK) activity in a dose-response manner, through 5-HT(2A) receptor subtype. Maximal activation of the enzyme (2.5-fold compared to control) is achieved in the presence of 25pM 5-HT, increasing both PFK maximal velocity and affinity for the substrate fructose-6-phosphate. These effects occur due to tyrosine phosphorylation of the enzyme that is 2-fold enhanced upon 5-HT stimulation of skeletal muscles preparation. Once 5-HT-induced tyrosine phosphorylation of PFK is prevented by genistein, a tyrosine kinase inhibitor, the hormone stimulatory effect on PFK is abrogated. Wortmannin, a phosphatidylinositol-3-kinase (PI3K) inhibitor, does not interfere on 5-HT-induced stimulation of PFK, supporting that the observed effects are independent on insulin signaling pathway. Furthermore, 5-HT promotes the association of PFK to the muscle f-actin, suggesting that the hormone alters PFK intracellular distribution, favoring its association to the cytoskeleton. Altogether, our results support evidences that 5-HT augments skeletal muscle glucose consumption through stimulation of glycolysis key regulatory enzyme, PFK, throughout tyrosine phosphorylation and intracellular redistribution of the enzyme.
authors.affiliation: Departamento de Fármacos, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Ilha do Fundão, Rio de Janeiro, RJ 21941-590, Brazil.
authors.forename: Wagner Santos
authors.initials: WS
authors.lastname: Coelho
authors.forename: Kelly Cristina
authors.initials: KC
authors.lastname: Costa
authors.forename: Mauro
authors.initials: M
authors.lastname: Sola-Penna
mesh_terms: D000818:Animals; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D010732:Phosphofructokinase-1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D012701:Serotonin; D014443:Tyrosine; D010732:Phosphofructokinase-1; D005947:Glucose