ERK/MAPK and PI3K signaling cascades modulate BDNF secretion by ASM cells. Nonasthmatic and asthmatic ASM cells were treated, under serum-free conditions, with 10 μM GPA-2A (Gq inhibitor), 2 μM PD98059 (ERK/MAPK inhibitor), or 50 nM wortmannin (PI3K inhibitor). Two hours later, cells were either exposed to medium or to 20 ng/ml TNF-α for 48 h, before cell supernatants were collected for quantifying BDNF secretion by ELISA. Inhibition of ERK or PI3K signals attenuated BDNF secretion substantially, in both nonasthmatic and asthmatic ASM cells. In the presence of these inhibitors, TNF-α did not enhance BDNF secretion in either of the cell types; n = 4 patients. *Significant difference from No Treatment-No TNF-α control, P < 0.05. #Significant difference between nonasthmatic and asthmatic cells, P < 0.05. $Significant difference between No Drug and Inhibitor systems, P < 0.05.