Calcium homeostasis in aging neurons

Abstract

The nervous system becomes increasingly vulnerable to insults and prone to dysfunction during aging. Age-related decline of neuronal function is manifested by the late onset of many neurodegenerative disorders, as well as by reduced signaling and processing capacity of individual neuron populations. Recent findings indicate that impairment of Ca(2+) homeostasis underlies the increased susceptibility of neurons to damage, associated with the aging process. However, the impact of aging on Ca(2+) homeostasis in neurons remains largely unknown. Here, we survey the molecular mechanisms that mediate neuronal Ca(2+) homeostasis and discuss the impact of aging on their efficacy. To address the question of how aging impinges on Ca(2+) homeostasis, we consider potential nodes through which mechanisms regulating Ca(2+) levels interface with molecular pathways known to influence the process of aging and senescent decline. Delineation of this crosstalk would facilitate the development of interventions aiming to fortify neurons against age-associated functional deterioration and death by augmenting Ca(2+) homeostasis.

Keywords: Golgi; endoplasmic reticulum; ion channel; long-term potentiation; mitochondria; neurodegeneration; neurotransmitter; synaptic plasticity.

FIGURE 1

Schematic representation of the main Ca²⁺ homeostatic machinery components in neurons. Individual, key components of calcium homeostatic mechanisms discussed in the text are shown. Arrows indicate direction of ion flux. ER, endoplasmic reticulum; IP3-R, inositol 3-phosphate receptor; NCX, sodium calcium exchanger; NMDA, N-methyl-D-aspartate; PMCA, plasma membrane Ca²⁺ ATPase; RyR, ryanodine receptor; SERCA, sarco(endo)plasmic reticulum Ca²⁺ ATPase; SPCA, secretory-pathway Ca²⁺-ATPase; VOCC, voltage-operated calcium channel.