Serotonin (5-hydroxytryptamine), a novel regulator of glucose transport inrat skeletal muscle

In this study we show that serotonin (5-hydroxytryptamine (5-HT)) causes a rapid stimulation in glucose uptake by similar to 50% in both L6 myotubes a nd isolated rat skeletal muscle. This activation is mediated via the 5-HT2A receptor, which is expressed in L6, rat, and human skeletal muscle. In L6 cells, expression of the 5-HT2A receptor is developmentally regulated based on the finding that receptor abundance increases by over 3-fold during dif ferentiation from myoblasts to myotubes, Stimulation of the 5-HT2A receptor using methylserotonin (m-HT), a selective 5-HT2A agonist, increased muscle glucose uptake in a manner similar to that seen in response to 5-HT. The a gonist-mediated stimulation in glucose uptake was attributable to an increa se in the plasma membrane content of GLUT1, GLUT3, and GLUT4. The stimulato ry effects of 5-HT and m-HT were suppressed in the presence of submicromola r concentrations of ketanserin (a selective 5-HT2A antagonist) providing fu rther evidence that the increase in glucose uptake was specifically mediate d via the 5-HT2A receptor. Treatment of L6 cells with insulin resulted in t yrosine phosphorylation of IRS1, increased cellular production of phosphati dylinositol 3,4,5-phosphate and a 41-fold activation in protein kinase B (P KB/Akt) activity. In contrast, m-HT did not modulate IRS1, phosphoinositide 3-kinase, or PKB activity. The present results indicate that rat and human skeletal muscle both express the 5-HT2A receptor and that 5-HT and specifi c 5-HT2A agonists can rapidly stimulate glucose uptake in skeletal muscle b y a mechanism which does not depend upon components that participate in the insulin signaling pathway.