title: SK2 channels regulate mitochondrial respiration and mitochondrial Ca2+uptake.
abstract: Mitochondrial calcium ([Ca2+]m) overload and changes in mitochondrial metabolism are key players in neuronal death. Small conductance calcium-activated potassium (SK) channels provide protection in different paradigms of neuronal cell death. Recently, SK channels were identified at the inner mitochondrial membrane, however, their particular role in the observed neuroprotection remains unclear. Here, we show a potential neuroprotective mechanism that involves attenuation of [Ca2+]muptake upon SK channel activation as detected by time lapse mitochondrial Ca2+measurements with the Ca2+-binding mitochondria-targeted aequorin and FRET-based [Ca2+]mprobes. High-resolution respirometry revealed a reduction in mitochondrial respiration and complex I activity upon pharmacological activation and overexpression of mitochondrial SK2 channels resulting in reduced mitochondrial ROS formation. Overexpression of mitochondria-targeted SK2 channels enhanced mitochondrial resilience against neuronal death, and this effect was inhibited by overexpression of a mitochondria-targeted dominant-negative SK2 channel. These findings suggest that SK channels provide neuroprotection by reducing [Ca2+]muptake and mitochondrial respiration in conditions, where sustained mitochondrial damage determines progressive neuronal death.
authors.affiliation: Institute of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg, Germany.|Faculty of Science and Engineering, Groningen Research Institute of Pharmacy, Behavioural and Cognitive Neurosciences (BCN), Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands.
authors.forename: Birgit
authors.initials: B
authors.lastname: Honrath
authors.affiliation: Institute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, Marburg, Germany.
authors.forename: Lina
authors.initials: L
authors.lastname: Matschke
authors.affiliation: Faculty of Science and Engineering, Groningen Research Institute of Pharmacy, Behavioural and Cognitive Neurosciences (BCN), Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands.
authors.forename: Tammo
authors.initials: T
authors.lastname: Meyer
authors.affiliation: Institute of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Magerhans
authors.affiliation: Gene Center/Department of Biochemistry, Ludwig-Maximilians Universität München, Munich, Germany.|Institute for Obesity and Diabetes, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Perocchi
authors.affiliation: Institute of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg, Germany.
authors.forename: Goutham K
authors.initials: GK
authors.lastname: Ganjam
authors.affiliation: Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health GmbH, Neuherberg, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Zischka
authors.affiliation: Institute of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg, Germany.
authors.forename: Cornelius
authors.initials: C
authors.lastname: Krasel
authors.affiliation: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics & Systems Biology Center for Energy Metabolism and Ageing, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Gerding
authors.affiliation: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics & Systems Biology Center for Energy Metabolism and Ageing, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Bakker
authors.affiliation: Institute of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Bünemann
authors.affiliation: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Strack
authors.affiliation: Institute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, Marburg, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Decher
authors.affiliation: Institute of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Culmsee
authors.affiliation: Institute of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg, Germany.|Faculty of Science and Engineering, Groningen Research Institute of Pharmacy, Behavioural and Cognitive Neurosciences (BCN), Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands.
authors.forename: Amalia M
authors.initials: AM
authors.lastname: Dolga
mesh_terms: D000331:Aequorin / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D042967:Electron Transport Complex I / Q000235:genetics* / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010091:Oximes / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D061251:Primary Cell Culture; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: C493327:6,7-dichloro-1H-indole-2,3-dione 3-oxime; D007211:Indoles; C496898:Kcnn2 protein, mouse; D010091:Oximes; D011720:Pyrazoles; D011743:Pyrimidines; D051640:Small-Conductance Calcium-Activated Potassium Channels; C552889:cyclohexyl-(2-(3,5-dimethylpyrazol-1-yl)-6-methylpyrimidin-4-yl)amine; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D001030:Apamin; D000331:Aequorin; D042967:Electron Transport Complex I; D002118:Calcium