Neuronal Calcium Homeostasis and Dysregulation

Abstract

The calcium ion (Ca 2+ ) is the main second messenger that helps to transmit depolarization status and synaptic activity to the biochemical machinery of a neuron. These features make Ca 2+ regulation a critical process in neurons, which have developed extensive and intricate Ca 2+ signaling pathways. High intensity Ca 2+ signaling necessitates high ATP consumption to restore basal (low) intracellular Ca 2+ levels after Ca 2+ influx through plasma membrane receptor and voltage-dependent ion channels. Ca 2+ influx may also lead to increased generation of mitochondrial reactive oxygen species (ROS). Impaired abilities of neurons to maintain cellular energy levels and to suppress ROS may impact Ca 2+ signaling during aging and in neurodegenerative disease processes. This review focuses on mitochondrial and endoplasmic reticulum Ca 2+ homeostasis and how they relate to synaptic Ca 2+ signaling processes, neuronal energy metabolism, and ROS generation. Also, the contribution of altered Ca 2+ signaling to neurodegeneration during aging will be considered. Advances in understanding the molecular regulation of Ca 2+ homeostasis and how it is perturbed in neurological disorders may lead to therapeutic strategies that modulate neuronal Ca 2+ signaling to enhance function and counteract disease processes.

Convergent Ca 2+ and Zn 2+ signaling regulates apoptotic Kv2.1 K + currents

“…Indeed, Ca 2+ deregulation has been associated with a variety of detrimental processes in neurons, including mitochondrial dysfunction (2), generation of reactive oxygen species (3), and activation of apoptotic signaling cascades (4). More recently, zinc, a metal crucial for proper cellular functioning (5), has been found to be closely linked to many of the injurious conditions in which Ca 2+ had been thought to play a prominent role (6)(7)(8)(9)(10).…”

Adverse Outcome Pathway on binding of agonists to ionotropic glutamate receptors in adult brain leading to excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment

“…In the case of Ca 2+ overload, mitochondria are not able to buffer the excess of Ca 2+ that leads to mitochondrial dysfunction measured by the increased generation of reactive oxygen species (ROS), triggering mitochondrial permeability transition pore opening (Choi et al, 2013) and reduced ATP production (reviewed in Gleichmann and Mattson, 2011).…”

“…Ca 2+ overload besides of being detrimental to mitochondrial energy production can also induce mitochondrial ROS generation. A number of possible mechanisms have been suggested by which Ca 2+ overload can increase ROS production including: 1) stimulated increase of metabolic rate by Ca 2+ , 2) stimulated nitric oxide production by Ca 2+ , 3) Ca 2+ induced cytochrome c dissociation, 4) Ca 2+ induced cardiolipin peroxidation, 5) Ca 2+ induced mitochondrial permeability transition pore (MPTP) opening with release of cytochrome c (leading to apoptosome formation and caspase-3 activation)and apoptosis inducing factor (AIF), decreased level of reduced glutathione (GSH), the antioxidative enzymes, and 6) Ca 2+ -calmodulin dependent protein kinase activation (reviewed in Peng and Jou, 2010;Gleichmann and Mattson, 2011). It is worth mentioning that mitochondrial ROS increase is capable of modulating Ca 2+ dynamics causing further increase of Ca 2+ levels.…”

Mitochondria and the central nervous system: searching for a pathophysiological basis of psychiatric disorders

“…18,49 Calcium (Ca 2+ ) is the principal second messenger that contributes to the regulation of both neurotransmission and short-and long-term neuronal plasticity in the brain. The role of Ca 2+ signals in apoptosis has been further reinforced by the demonstration that antiapoptotic proteins (such as Bcl-2) decrease Ca 2+ levels in the endoplasmic reticulum (ER) and reduce cytosolic and mitochondrial Ca 2+ responses to extracellular stimuli by increasing the leak of Ca 2+ from the ER.…”