Serotonin stimulates mouse skeletal muscle 6-phosphofructo-1-kinase through tyrosine-phosphorylation of the enzyme altering its intracellular localization.
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.
Coelho
Wagner Santos
WS
Departamento de Fármacos, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Ilha do Fundão, Rio de Janeiro, RJ 21941-590, Brazil.
Costa
Kelly Cristina
KC
Sola-Penna
Mauro
M
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
D047428:Protein Kinase Inhibitors; D012701:Serotonin; D014443:Tyrosine; D010732:Phosphofructokinase-1; D005947:Glucose