We previously reported that 17β-estradiol (E2) improves long term potentiation (LTP) in hippocampal neurons after global ischemia in rat. In the present study, we investigated if E2 can directly modulate the activity of neuronal KCNQ2/3 channels, the molecular entity of neuronal M-current in hippocampus, expressed in the PC-12 cells. We found that exogenous E2 inhibits the KCNQ2/3 channels in a dose-dependent fashion. The minimal inhibitory concentration of E2 is 10 µ M . At testing membrane potential of +90 mV, the whole cell current density was reduced to 56.5, 49.3 and 31.9% of the control by 50, 20 and 10 µ M of E2, respectively. The voltage-dependency of the KCNQ2/3 currents was also affected. E2 at 10, 20 and 50 µ M shifted the half maximal activation voltage ( V _1/2) from 13.8±2.3 mV ( n =12) to 20.6±1.9 mV ( n =8, p <0.05), 26.0±1.9 mV ( n =8, p <0.001) and 27.6±3.5 mV ( n =8, p <0.001), respectively. Our data indicate that exogenous E2 can directly affect the activity of KCNQ2/3 channels at pharmacological levels via a non-genomic pathway.