Specific enhancement of SK channel activity selectively potentiates the afterhyperpolarizing current I(AHP) and modulates the firing properties of hippocampal pyramidal neurons.
SK channels are Ca2+-activated K+ channels that underlie after hyperpolarizing (AHP) currents and contribute to the shaping of the firing patterns and regulation of Ca2+ influx in a variety of neurons. The elucidation of SK channel function has recently benefited from the discovery of SK channel enhancers, the prototype of which is 1-EBIO. 1-EBIO exerts profound effects on neuronal excitability but displays a low potency and limited selectivity. This study reports the effects of DCEBIO, an intermediate conductance Ca2+-activated K+ channel modulator, and the effects of the recently identified potent SK channel enhancer NS309 on recombinant SK2 channels, neuronal apamin-sensitive AHP currents, and the excitability of CA1 neurons. NS309 and DCEBIO increased the amplitude and duration of the apamin-sensitive afterhyperpolarizing current without affecting the slow afterhyperpolarizing current in contrast to 1-EBIO. The potentiation by DCEBIO and NS309 was reversed by SK channel blockers. In current clamp experiments, NS309 enhanced the medium afterhyperpolarization (but not the slow afterhyperpolarization sAHP) and profoundly affected excitability by facilitating spike frequency adaptation in a frequency-independent manner. The potent and specific effect of NS309 on the excitability of CA1 pyramidal neurons makes this compound an ideal tool to assess the role of SK channels as possible targets for the treatment of disorders linked to neuronal hyperexcitability.
Pedarzani
Paola
P
Department of Physiology, University College London, Gower Street, London WC1E 6BT, United Kingdom. P.Pedarzani@ucl.ac.uk
McCutcheon
Jaime E
JE
Rogge
Gregor
G
Jensen
Bo Skaaning
BS
Christophersen
Palle
P
Hougaard
Charlotte
C
Strøbaek
Dorte
D
Stocker
Martin
M
D000818:Animals; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D051658:KCNQ2 Potassium Channel / Q000378:metabolism; D051659:KCNQ3 Potassium Channel / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000737:chemistry / Q000502:physiology*; D013430:Sulfate Adenylyltransferase / Q000378:metabolism; D009435:Synaptic Transmission; D013997:Time Factors
D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D009097:Multienzyme Complexes; D011994:Recombinant Proteins; D051640:Small-Conductance Calcium-Activated Potassium Channels; C113697:sulfurylase kinase; D017853:Phosphotransferases (Alcohol Group Acceptor); D013430:Sulfate Adenylyltransferase; D011188:Potassium; D002118:Calcium