title: KCa2 channels activation prevents [Ca2+]i deregulation and reduces neuronal death following glutamate toxicity and cerebral ischemia.
abstract: Exacerbated activation of glutamate receptor-coupled calcium channels and subsequent increase in intracellular calcium ([Ca2+]i) are established hallmarks of neuronal cell death in acute and chronic neurological diseases. Here we show that pathological [Ca2+]i deregulation occurring after glutamate receptor stimulation is effectively modulated by small conductance calcium-activated potassium (KCa2) channels. We found that neuronal excitotoxicity was associated with a rapid downregulation of KCa2.2 channels within 3 h after the onset of glutamate exposure. Activation of KCa2 channels preserved KCa2 expression and significantly reduced pathological increases in [Ca2+]i providing robust neuroprotection in vitro and in vivo. These data suggest a critical role for KCa2 channels in excitotoxic neuronal cell death and propose their activation as potential therapeutic strategy for the treatment of acute and chronic neurodegenerative disorders.
authors.affiliation: Institut für Pharmakologie und Klinische Pharmazie, Fachbereich Pharmazie, Philipps-Universität Marburg, Marburg, Germany.
authors.forename: A M
authors.initials: AM
authors.lastname: Dolga
authors.forename: N
authors.initials: N
authors.lastname: Terpolilli
authors.forename: F
authors.initials: F
authors.lastname: Kepura
authors.forename: I M
authors.initials: IM
authors.lastname: Nijholt
authors.forename: H-G
authors.initials: HG
authors.lastname: Knaus
authors.forename: B
authors.initials: B
authors.lastname: D'Orsi
authors.forename: J H M
authors.initials: JH
authors.lastname: Prehn
authors.forename: U L M
authors.initials: UL
authors.lastname: Eisel
authors.forename: T
authors.initials: T
authors.lastname: Plant
authors.forename: N
authors.initials: N
authors.lastname: Plesnila
authors.forename: C
authors.initials: C
authors.lastname: Culmsee
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D020013:Calcium Signaling; D018929:Cell Culture Techniques; D016923:Cell Death; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism* / Q000633:toxicity; D007211:Indoles / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C493327:6,7-dichloro-1H-indole-2,3-dione 3-oxime; D018690:Excitatory Amino Acid Agonists; D007211:Indoles; D018696:Neuroprotective Agents; D010091:Oximes; D051640:Small-Conductance Calcium-Activated Potassium Channels; D018698:Glutamic Acid; D016202:N-Methylaspartate