Functional reduction of SK3-mediated currents precedes AMPA-receptor-mediated excitotoxicity in dopaminergic neurons.
In primary cultures of mesencephalon small-conductance calcium-activated potassium channels (SK) are expressed in dopaminergic neurons. We characterized SK-mediated currents (I(SK)) in this system and evaluated their role on homeostasis against excitotoxicity. I(SK) amplitude was reduced by the glutamatergic agonist AMPA through a reduction in SK channel number in the membrane. Blockade of I(SK) for 12 h with apamin or NS8593 reduced the number of dopaminergic neurons in a concentration-dependent manner. The effect of apamin was not additive to AMPA toxicity. On the other hand, two I(SK) agonists, 1-EBIO and CyPPA, caused a significant reduction of spontaneous loss of dopaminergic neurons. 1-EBIO reversed the effects of both AMPA and apamin as well. Thus, I(SK) influences survival and differentiation of dopaminergic neurons in vitro, and is part of protective homeostatic responses, participating in a rapidly acting negative feedback loop coupling calcium levels, neuron excitability and cellular defenses. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
Laboratory of Brain Development, Modulation and Repair, Brigham and Women's Hospital, Harvard Medical School, MA 02115, USA.
Bruno A
BA
Benítez
Helen M
HM
Belálcazar
Agustín
A
Anastasía
Daniel T
DT
Mamah
Charles F
CF
Zorumski
Daniel H
DH
Mascó
Daniel G
DG
Herrera
Gabriel A
GA
de Erausquin
D015057:1-Naphthylamine / Q000031:analogs & derivatives / Q000633:toxicity; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001030:Apamin / Q000633:toxicity; D001562:Benzimidazoles / Q000494:pharmacology; D002120:Calcium Channel Agonists / Q000494:pharmacology; D018929:Cell Culture Techniques; D004298:Dopamine / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000819:agonists; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity; D018408:Patch-Clamp Techniques; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D011954:Receptors, Dopamine / Q000187:drug effects; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology*
C515166:(R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphthylamine; D001562:Benzimidazoles; D002120:Calcium Channel Agonists; D018690:Excitatory Amino Acid Agonists; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; C496901:Kcnn3 protein, rat; D009498:Neurotoxins; D011720:Pyrazoles; D011743:Pyrimidines; D018091:Receptors, AMPA; D011954:Receptors, Dopamine; D051640:Small-Conductance Calcium-Activated Potassium Channels; C552889:cyclohexyl-(2-(3,5-dimethylpyrazol-1-yl)-6-methylpyrimidin-4-yl)amine; D001030:Apamin; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D015057:1-Naphthylamine; C102635:1-ethyl-2-benzimidazolinone; D004298:Dopamine