title: Loss of calcium/calmodulin-dependent protein kinase II activity in cortical astrocytes decreases glutamate uptake and induces neurotoxic release of ATP.
abstract: The extent of calcium/calmodulin-dependent protein kinase II (CaMKII) inactivation in the brain after ischemia correlates with the extent of damage. We have previously shown that a loss of CaMKII activity in neurons is detrimental to neuronal viability by inducing excitotoxic glutamate release. In the current study we extend these findings to show that the ability of astrocytes to buffer extracellular glutamate is reduced when CaMKII is inhibited. Furthermore, CaMKII inhibition in astrocytes is associated with the rapid onset of intracellular calcium oscillations. Surprisingly, this rapid calcium influx is blocked by the N-type calcium channel antagonist, ω-conotoxin. Although the function of N-type calcium channels within astrocytes is controversial, these voltage-gated calcium channels have been linked to calcium-dependent vesicular gliotransmitter release. When extracellular glutamate and ATP levels are measured after CaMKII inhibition within our enriched astrocyte cultures, no alterations in glutamate levels are observed, whereas ATP levels in the extracellular environment significantly increase. Extracellular ATP accumulation associated with CaMKII inhibition contributes both to calcium oscillations within astrocytes and ultimately cortical neuron toxicity. Thus, a loss of CaMKII signaling within astrocytes dysregulates glutamate uptake and supports ATP release, two processes that would compromise neuronal survival after ischemic/excitotoxic insults.
authors.affiliation: Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Ashpole
authors.affiliation: Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Aarti R
authors.initials: AR
authors.lastname: Chawla
authors.affiliation: Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Martin
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Brustovetsky
authors.affiliation: Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Nickolay
authors.initials: N
authors.lastname: Brustovetsky
authors.affiliation: Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202. Electronic address: ahudmon@iupui.edu.
authors.forename: Andy
authors.initials: A
authors.lastname: Hudmon
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000166:cytology*; D020864:Calcium Channels, N-Type / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002450:Cell Communication; D002470:Cell Survival; D018920:Coculture Techniques; D018698:Glutamic Acid / Q000378:metabolism*; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020864:Calcium Channels, N-Type; D009498:Neurotoxins; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: CaMKII; Calcium Signaling; Glia; Glutamate; Neurodegeneration; Neuronal-Glial Communication
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