Pre- and postsynaptic activation of M-channels by a novel opener dampens neuronal firing and transmitter release.
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 (EC(50) = 18 muM) 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 after depolarization 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 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.
Peretz
Asher
A
Dept. of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Sheinin
Anton
A
Yue
Cuiyong
C
Degani-Katzav
Nurit
N
Gibor
Gilad
G
Nachman
Rachel
R
Gopin
Anna
A
Tam
Eyal
E
Shabat
Doron
D
Yaari
Yoel
Y
Attali
Bernard
B
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007476:Ionophores / Q000138:chemical synthesis / Q000494:pharmacology; D051658:KCNQ2 Potassium Channel / Q000819:agonists / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D009420:Nervous System / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009924:Organ Culture Techniques; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D062367:ortho-Aminobenzoates / Q000737:chemistry
D007476:Ionophores; D051658:KCNQ2 Potassium Channel; D018377:Neurotransmitter Agents; D062367:ortho-Aminobenzoates; C001209:fenamic acid