Pre- and postsynaptic activation of M-channels by a novel opener dampens neuronal firing and transmitter release

Asher Peretz, Anton Sheinin, Cuiyong Yue, Nurit Degani-Katzav, Gilad Gibor, Rachel Nachman, Anna Gopin, Eyal Tam, Doron Shabat, Yoel Yaari, Bernard Attali

Research output: Contribution to journalArticlepeer-review

Abstract

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 IKS K+ currents as well as NR1/NR2B, AMPA, and GABAA 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 postsynaptic currents. Activation of M-channels also decreased the frequency of miniature excitatory (mEPSC) and inhibitory (mIPSC) postsynaptic currents without affecting their amplitude and waveform, thus suggesting that Mchannels 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.

Original languageEnglish
Pages (from-to)283-295
Number of pages13
JournalJournal of Neurophysiology
Volume97
Issue number1
DOIs
StatePublished - Jan 2007

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