Activation of SK channels inhibits epileptiform bursting in hippocampal CA3 neurons.
The role of calcium-activated potassium channels in the regulation of neuronal hyperexcitability, as in epilepsy, is unclear. To examine this issue, we have used the acute hippocampal slice model of epileptiform activity to investigate the effects of an enhancer of SK channel activity, 1-ethyl-benzimidazolinone (EBIO). That EBIO is an SK channel modulator was confirmed by its potentiation of hSK1, hSK2, hSK3 and hIK currents (EC(50) values in the range of 130-870 microM) and its apamin (1 microM) sensitive reduction of the number of action potentials fired in CA3 pyramidal neurons in response to a depolarizing current step. In addition, while EBIO did not significantly affect electrically evoked glutamatergic synaptic transmission, it did inhibit epileptiform activity (IC(50) values in the range of 150-325 microM) induced by (1) modifying the extracellular ionic environment by removing extracellular Mg(2+) or elevating extracellular K(+) from 3.0 to 8.5 mM and (2) disinhibiting the slice using 3 mM pentylenetetrazol or combined application of 10 microM gabazine and 10 microM CGP55845. Furthermore, its inhibitory effect in the full disinhibition model of epileptiform activity (10 microM gabazine + 10 microM CGP55845) was occluded by the SK channel blocker apamin (300 nM-1 microM) which in its own right increased the duration and reduced the frequency of individual epileptiform bursts. In conclusion, compounds that enhance the activation of small conductance Ca(2+) -activated K(+) channels are effective inhibitors of epileptiform activity in vitro.
Lappin
Sarah C
SC
Neurology and GI CEDD, GlaxoSmithKline, New Frontiers Science Park North, Third Avenue, Harlow, Essex CM19 5AW, UK. Sarah.C.Lappin@gsk.com
Dale
Tim J
TJ
Brown
Jon T
JT
Trezise
Derek J
DJ
Davies
Ceri H
CH
D000818:Animals; D001030:Apamin / Q000494:pharmacology; D001562:Benzimidazoles; D016466:CHO Cells; D002120:Calcium Channel Agonists; D002460:Cell Line; D006224:Cricetinae; D004827:Epilepsy / Q000503:physiopathology*; D005071:Evoked Potentials / Q000187:drug effects; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects / Q000502:physiology; D018757:GABA Modulators / Q000494:pharmacology; D006624:Hippocampus / Q000503:physiopathology*; D006801:Humans; D008275:Magnesium Deficiency / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008959:Models, Neurological; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology*; D051381:Rats; D011994:Recombinant Proteins
D001562:Benzimidazoles; D002120:Calcium Channel Agonists; D018757:GABA Modulators; D024681:Potassium Channels, Calcium-Activated; D011994:Recombinant Proteins; D001030:Apamin; C102635:1-ethyl-2-benzimidazolinone; D011188:Potassium