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 Ca ²⁺ signaling pathways. High intensity Ca²⁺ signaling necessitates high ATP consumption to restore basal (low) intracellular Ca ²⁺ 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 Ca ²⁺ 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.