Genistein, an isoflavonoid natural product, is widely used to inhibit protein tyrosine kinase (PTK). In the present study, we investigated the possible influence of genistein on alpha (1)-adrenoceptors (AR) in cultured C2C12 cells. Genistein enhanced the uptake of radioactive glucose into C2C12 cells in a concentration-dependent manner. Similar results were also observed in samples treated with daidzein, the inactive congener for PTK inhibition. The effect of genistein on alpha (1)-AR was further characterized using the displacement of [ (3)H]prazosin binding in C2C12 cells. The increase in radioactive glucose uptake by genistein was abolished by RS17053 at a concentration sufficient to block alpha (1A)-AR. The pharmacological inhibition of phospholipase C (PLC) by U73122 resulted in a concentration-dependent reduction of genistein-stimulated glucose uptake in C2C12 cells. This inhibition by U73122 was specific because the inactive congener, U73343, failed to modify the action of genistein. Moreover, genistein can activate alpha (1A)-AR at a concentration (1 micromol/L) lower than that (50 micromol/L) needed to abolish the insulin-stimulated phosphorylation of PTK. The obtained data indicate an activation of alpha (1A)-AR by genistein to increase the glucose uptake into C2C12 cells and this supports the application of genistein as a TK inhibitor.