Neuronal Calcium Homeostasis and Dysregulation

The calcium ion (Ca2+) is the main second messenger that helps to transmit depolarization status and synaptic activity to the biochemical machinery of a neuron. These features make Ca2+ regulation a critical process in neurons, which have developed extensive and intricate Ca2+ signaling pathways. High intensity Ca2+ signaling necessitates high ATP consumption to restore basal (low) intracellular Ca2+ levels after Ca2+ influx through plasma membrane receptor and voltage-dependent ion channels. Ca2+ 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 Ca2+ signaling during aging and in neurodegenerative disease processes. This review focuses on mitochondrial and endoplasmic reticulum Ca2+ homeostasis and how they relate to synaptic Ca2+ signaling processes, neuronal energy metabolism, and ROS generation. Also, the contribution of altered Ca2+ signaling to neurodegeneration during aging will be considered. Advances in understanding the molecular regulation of Ca2+ homeostasis and how it is perturbed in neurological disorders may lead to therapeutic strategies that modulate neuronal Ca2+ signaling to enhance function and counteract disease processes. Antioxid. Redox Signal. 14, 1261-1273.