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Review
, 14 (7), 1275-88

Calcium Dysregulation and Homeostasis of Neural Calcium in the Molecular Mechanisms of Neurodegenerative Diseases Provide Multiple Targets for Neuroprotection

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Review

Calcium Dysregulation and Homeostasis of Neural Calcium in the Molecular Mechanisms of Neurodegenerative Diseases Provide Multiple Targets for Neuroprotection

Gregor Zündorf et al. Antioxid Redox Signal.

Abstract

The intracellular free calcium concentration subserves complex signaling roles in brain. Calcium cations (Ca(2+)) regulate neuronal plasticity underlying learning and memory and neuronal survival. Homo- and heterocellular control of Ca(2+) homeostasis supports brain physiology maintaining neural integrity. Ca(2+) fluxes across the plasma membrane and between intracellular organelles and compartments integrate diverse cellular functions. A vast array of checkpoints controls Ca(2+), like G protein-coupled receptors, ion channels, Ca(2+) binding proteins, transcriptional networks, and ion exchangers, in both the plasma membrane and the membranes of mitochondria and endoplasmic reticulum. Interactions between Ca(2+) and reactive oxygen species signaling coordinate signaling, which can be either beneficial or detrimental. In neurodegenerative disorders, cellular Ca(2+)-regulating systems are compromised. Oxidative stress, perturbed energy metabolism, and alterations of disease-related proteins result in Ca(2+)-dependent synaptic dysfunction, impaired plasticity, and neuronal demise. We review Ca(2+) control processes relevant for physiological and pathophysiological conditions in brain tissue. Dysregulation of Ca(2+) is decisive for brain cell death and degeneration after ischemic stroke, long-term neurodegeneration in Alzheimer's disease, Parkinson's disease, Huntington's disease, inflammatory processes, such as in multiple sclerosis, epileptic sclerosis, and leucodystrophies. Understanding the underlying molecular processes is of critical importance for the development of novel therapeutic strategies to prevent neurodegeneration and confer neuroprotection.

Figures

FIG. 1.
FIG. 1.
Ca2+ homeostasis in brain under normal physiological conditions. Stimuli induce the entry of external Ca2+ via CaV, TRP channels, and ROC. Activation of GPCR and other signals enable release of internal Ca2+ from the ER by formation of second messengers that open channels of receptors for InsP3R and RyR. The latter pathway is also activated by Ca2+ through calcium influx. Ca2+ depletion of intracellular ER Ca2+ stores further signals to the activation of capacitative Ca2+ entry from the Ca2+ sensor STIM to Orai/TRP channels. Mitochondria sequester Ca2+ through the uniporter MCU, and Ca2+ is released back into the cytosol by the NCXmito. In conditions of acute or lasting damage, Ca2+ is spilled out by the mPTP, which is shown in Figures 2 and 3; this pore might also have some physiological function, replenishing [Ca2+]i. KCa contribute to reducing overexcitation by hyperpolarizing the plasma membrane. Ca2+ is removed from the cell by extrusion of Ca2+ to the outside, mediated by the NCX and the PMCA. The SERCA pumps Ca2+ back into the ER. Intracellular Ca2+ spatiotemporally binds to buffers and effectors and, thus, activates a plethora of cellular processes. Ca2+, calcium cations; [Ca2+]i, intracellular free Ca2+ concentration; CaV, voltage-gated Ca2+ channels; TRP, transient receptor potential; ROC, receptor-operated channels; GPCR, G protein-coupled receptors; ER, endoplasmic reticulum; InsP3R, inositol(1,4,5)-trisphosphate receptor; RyR, ryanodine receptor; MCU, mitochondrial Ca2+ uniporter; NCX, Na+/Ca2+ exchanger; NCXmito, mitochondrial exchanger; mPTP, mitochondrial permeability transition pore; KCa, Ca2+-activated K+ channels; PMCA, plasma-membrane Ca2+-ATPase; SERCA sarco(endo)plasmic reticulum Ca2+-ATPase; STIM, stromal interacting molecule. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).
FIG. 2.
FIG. 2.
Perturbed brain Ca2+ homeostasis in Alzheimer's disease due to mutations of several proteins and formation of protein aggregate deposits. Several pathways lead to [Ca2+]i overload. Thus, Aβ oligomers form pores in the plasma membrane through which Ca2+ passes into the cytoplasm. Aβ can also interact with Fe2+ and Cu+ to generate HOO and OH, resulting in membrane lipid peroxidation that impairs the function of PMCA. As a result, the plasma membrane becomes depolarized; NMDAR and CaV open and cause flux of Ca2+ into the cytoplasm. Interaction of reelin with the ApoER2 enhances Ca2+ influx through NMDAR by a mechanism involving a SFk. Increased [Ca2+]i further increases [Ca2+]i by calpain-mediated inhibition of PMCA and nNOS-induced activation of TRPM7. Aβ acts on mitochondria, to cause Ca2+ overload-increased ROS production, depolarization, and decreased ATP production. Mutations of PS result in excessive accumulation of Ca2+ in the ER via SERCA and, thus, enhance Ca2+ release through RyR and InsP3R channels. Further, the intracellular APP domain AICD, which is generated by proteolysis from amyloid precursor protein translocates to the nucleus and alters Ca2+-dependent gene transcription. AICD, amyloid intracellular C-terminal domain; Aβ, β-amyloid; NMDAR, N-methyl-D-aspartate receptor; ApoER2, apolipoprotein E receptor; SFk, src family tyrosine kinsase; NO, nitric oxide; nNOS, neuronal NO synthase; ROS, reactive oxygen species; PS, presenilins; APP, Aβ precursor protein; ΔΨc, cytosolic membrane potential; ΔΨm, mitochondrial membrane potential. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).
FIG. 3.
FIG. 3.
Perturbation of neural Ca2+ homeostasis under ischemic conditions. Neuronal and glial cell death is primarily mediated by oxidative stress and excess glutamate. Ca2+ entry through NMDAR mainly triggers the excitotoxic Ca2+ overload. As a result, calpains are activated, which inactivate by cleavage both NCX3 and PMCA. This precludes the capability to remove accumulated Ca2+. High [Ca2+]i induces stimulation of nNOS, which leads to production of ONOO•− and to the feedforward activation of TRPM7 currents. The decrease in [Ca2+] in the extracellular space disinhibits Ca2+-sensing channels, such as KCa3.1, leading to a further membrane depolarization. As a result of high [Ca2+]i, excessive rise of intramitochondrial Ca2+ triggers the opening of the mPTP. Mitochondria also release Ca2+ via NCXmito. This induces a depletion of ATP. Under ischemic conditions, the mode of operation of NCXmito is reverted. Then, the NCXmito acts as an influx pathway for Ca2+ into the mitochondrial matrix. ROS induce a high activity response of RyR2 and thus amplify the increase of [Ca2+]i. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).

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