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Ca2+/calmodulin-dependent protein kinase II and Dimethyl Sulfoxide affect the sealing frequencies of transected hippocampal neurons.

ABSTRACT: Traumatic injury often results in axonal severance, initiating obligatory Wallerian degeneration of distal segments, whereas proximal segments often survive. Calcium ion (Ca2+ ) influx at severed proximal axonal ends activates pathways that can induce apoptosis. However, this same Ca2+ -influx also activates multiple parallel pathways that seal the plasmalemma by inducing accumulation and fusion of vesicles at the lesion site that reduce Ca2+ -influx and enhance survival. We examined whether various inhibitors of Ca2+ /calmodulin-dependent protein kinases (CaMKs), and/or dimethyl sulfoxide (DMSO), a common solvent for biologically active substances, affected the ability of a hippocampal-derived neuronal cell line (B104 cells) to seal membrane damage following axotomy. Axolemmal sealing frequencies were assessed at different transection distances from the axon hillock and at various times after Ca2+ -influx (PC times) by observing whether transected cells took-up fluorescent dyes. Inhibition of CaMKII by tatCN21 and KN-93, but not inhibition of CaMKI and CaMKIV by STO-609, affected axonal sealing frequencies. That is, CaMKII is a component of previously reported parallel pathways that induce membrane sealing, whereas CaMKI and CaMKIV are not involved. The effects of these CaMKII inhibitors on plasmalemmal sealing depended on their mechanism of inhibition, transection distance, and PC time. DMSO at low concentrations (90?µM-28?mM or 0.00064%-0.2% v/v) significantly increased membrane-sealing frequencies at most PC times and transection distances, possibly by permeabilizing the plasmalemma to Ca2+ . Inhibition of CaMKII, DMSO, PC time, and the transection distance significantly affect plasmalemmal sealing that is critical to somal survival in traumatic lesions.

SUBMITTER: Poon AD

PROVIDER: S-EPMC5980716 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Ca2+/calmodulin-dependent protein kinase II and Dimethyl Sulfoxide affect the sealing frequencies of transected hippocampal neurons.

Poon Andrew D AD McGill Sarah H SH Bhupanapadu Sunkesula Solomon Raju SR Burgess Zachary S ZS Dunne Patrick J PJ Kang Edward E EE Bittner George D GD

Journal of neuroscience research 20180326 7

Traumatic injury often results in axonal severance, initiating obligatory Wallerian degeneration of distal segments, whereas proximal segments often survive. Calcium ion (Ca2+ ) influx at severed proximal axonal ends activates pathways that can induce apoptosis. However, this same Ca2+ -influx also activates multiple parallel pathways that seal the plasmalemma by inducing accumulation and fusion of vesicles at the lesion site that reduce Ca2+ -influx and enhance ...[more]

PMID: 29577375

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Project description:Aging is often associated with a cognitive decline and a susceptibility to neuronal damage. It is also the most important risk factor for neurodegenerative disorders, particularly Alzheimer's disease (AD). AD is related to an excess of neurotoxic oligomers of amyloid ? peptide (A?o); however, the molecular mechanisms are still highly controversial. Intracellular Ca2+ homeostasis plays an important role in the control of neuronal activity, including neurotransmitter release, synaptic plasticity, and memory storage, as well as neuron cell death. Recent evidence indicates that long-term cultures of rat hippocampal neurons, resembling aged neurons, undergo cell death after treatment with A?o, whereas short-term cultures, resembling young neurons, do not. These in vitro changes are associated with the remodeling of intracellular Ca2+ homeostasis with aging, thus providing a simplistic model for investigating Ca2+ remodeling in aging. In vitro aged neurons show increased resting cytosolic Ca2+ concentration, enhanced Ca2+ store content, and Ca2+ release from the endoplasmic reticulum (ER). Ca2+ transfer from the endoplasmic reticulum (ER) to mitochondria is also enhanced. Aged neurons also show decreased store-operated Ca2+ entry (SOCE), a Ca2+ entry pathway related to memory storage. At the molecular level, in vitro remodeling is associated with changes in the expression of Ca2+ channels resembling in vivo aging, including changes in N-methyl-D-aspartate NMDA receptor and inositol 1,4,5-trisphosphate (IP3) receptor isoforms, increased expression of the mitochondrial calcium uniporter (MCU), and decreased expression of Orai1/Stim1, the molecular players involved in SOCE. Additionally, A?o treatment exacerbates most of the changes observed in aged neurons and enhances susceptibility to cell death. Conversely, the solely effect of A?o in young neurons is to increase ER-mitochondria colocalization and enhance Ca2+ transfer from ER to mitochondria without inducing neuronal damage. We propose that cultured rat hippocampal neurons may be a useful model to investigate Ca2+ remodeling in aging and in age-related neurodegenerative disorders.

Dataset Information

Ca2+/calmodulin-dependent protein kinase II and Dimethyl Sulfoxide affect the sealing frequencies of transected hippocampal neurons.

Publications

Ca2+/calmodulin-dependent protein kinase II and Dimethyl Sulfoxide affect the sealing frequencies of transected hippocampal neurons.

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