The M-type K⁺ current (M-current), encoded by Kv7.2/3 (KCNQ2/3) K⁺ channels, plays a critical role in regulating neuronal excitability because it counteracts subthreshold depolarizations. Here we have characterized the functions of pre- and postsynaptic M-channels using a novel Kv7.2/3 channel opener, NH6, which we synthesized as a new derivative of N-phenylanthranilic acid. NH6 exhibits a good selectivity, as it does not affect Kv7.1 and I_KS K⁺ currents as well as NR1/NR2B, AMPA and GABA_A receptor-mediated currents. Superfusion of NH6 increased recombinant Kv7.2/3 current amplitude (EC₅₀ = 18 µM) by causing a hyperpolarizing shift of the voltage activation curve and by markedly slowing the deactivation kinetics. Activation of native M-currents by NH6 robustly reduced the number of evoked and spontaneous action potentials in cultured cortical, hippocampal and dorsal root ganglion neurons. In hippocampal slices, NH6 decreased somatically-evoked spike afterdepolarization of CA1 pyramidal neurons and induced regular firing in bursting neurons. Activation of M-channels by NH6, potently reduced the frequency of spontaneous excitatory and inhibitory post-synaptic currents. Activation of M-channels also decreased the frequency of miniature excitatory (mEPSC) and inhibitory (mIPSC) post-synaptic currents without affecting their amplitude and waveform, thus suggesting that M-channels presynaptically inhibit glutamate and GABA release. Our results suggest a role of presynaptic M-channels in the release of glutamate and GABA. They also indicate that M-channels act pre- and postsynaptically to dampen neuronal excitability.