title: Mitochondrial small conductance SK2 channels prevent glutamate-induced oxytosis and mitochondrial dysfunction.
abstract: Small conductance calcium-activated potassium (SK2/K(Ca)2.2) channels are known to be located in the neuronal plasma membrane where they provide feedback control of NMDA receptor activity. Here, we provide evidence that SK2 channels are also located in the inner mitochondrial membrane of neuronal mitochondria. Patch clamp recordings in isolated mitoplasts suggest insertion into the inner mitochondrial membrane with the C and N termini facing the intermembrane space. Activation of SK channels increased mitochondrial K(+) currents, whereas channel inhibition attenuated these currents. In a model of glutamate toxicity, activation of SK2 channels attenuated the loss of the mitochondrial transmembrane potential, blocked mitochondrial fission, prevented the release of proapoptotic mitochondrial proteins, and reduced cell death. Neuroprotection was blocked by specific SK2 inhibitory peptides and siRNA targeting SK2 channels. Activation of mitochondrial SK2 channels may therefore represent promising targets for neuroprotective strategies in conditions of mitochondrial dysfunction.
authors: Institut für Pharmakologie und Klinische Pharmazie, Fachbereich Pharmazie, Philipps-Universität Marburg, D-35032 Marburg, Germany. dolga@staff.uni-marburg.de
authors: Amalia M
authors: AM
authors: Dolga
authors: Michael F
authors: MF
authors: Netter
authors: Fabiana
authors: F
authors: Perocchi
authors: Nunzianna
authors: N
authors: Doti
authors: Lilja
authors: L
authors: Meissner
authors: Svenja
authors: S
authors: Tobaben
authors: Julia
authors: J
authors: Grohm
authors: Hans
authors: H
authors: Zischka
authors: Nikolaus
authors: N
authors: Plesnila
authors: Niels
authors: N
authors: Decher
authors: Carsten
authors: C
authors: Culmsee
mesh_terms: D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051336:Mitochondrial Membranes / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C496898:Kcnn2 protein, mouse; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010455:Peptides; D051640:Small-Conductance Calcium-Activated Potassium Channels; D018698:Glutamic Acid; D011188:Potassium