Age-dependent changes in Ca2+ homeostasis in peripheral neurones: implications for changes in function

Abstract

Calcium ions represent universal second messengers within neuronal cells integrating multiple cellular functions, such as release of neurotransmitters, gene expression, proliferation, excitability, and regulation of cell death or apoptotic pathways. The magnitude, duration and shape of stimulation-evoked intracellular calcium ([Ca2+]i) transients are determined by a complex interplay of mechanisms that modulate stimulation-evoked rises in [Ca2+]i that occur with normal neuronal function. Disruption of any of these mechanisms may have implications for the function and health of peripheral neurones during the aging process. This review focuses on the impact of advancing age on the overall function of peripheral adrenergic neurones and how these changes in function may be linked to age-related changes in modulation of [Ca2+]i regulation. The data in this review suggest that normal aging in peripheral autonomic neurones is a subtle process and does not always result in dramatic deterioration in their function. We present studies that support the idea that in order to maintain cell viability peripheral neurones are able to compensate for an age-related decline in the function of at least one of the neuronal calcium-buffering systems, smooth endoplasmic reticulum calcium ATPases, by increased function of other calcium-buffering systems, namely, the mitochondria and plasmalemma calcium extrusion. Increased mitochondrial calcium uptake may represent a 'weak point' in cellular compensation as this over time may contribute to cell death. In addition, we present more recent studies on [Ca2+]i regulation in the form of the modulation of release of calcium from smooth endoplasmic reticulum calcium stores. These studies suggest that the contribution of the release of calcium from smooth endoplasmic reticulum calcium stores is altered with age through a combination of altered ryanodine receptor levels and modulation of these receptors by neuronal nitric oxide containing neurones.

Fig. 1

(A) Representation of mechanisms that modulate stimulation-evoked [Ca²⁺]i transients in peripheral adrenergic nerves. Depolarization increases [Ca²⁺]i by rapid calcium influx through voltage-gated calcium channels. Calcium is rapidly attenuated via calcium-binding proteins and the residual calcium signal acting on ryanodine receptors (RyR) evoke release of calcium from the endoplasmic reticulum known as calcium-induced calcium release (CICR). The elevation in [Ca²⁺]i is controlled by a dynamic interplay of buffering systems: (1) smooth endoplasmic reticulum calcium ATPases (SERCA) sequestration into the ER that serves to buffer and refill ER calcium stores thus maintaining the ability of the neurone to undergo repetitive CICR; (2) mitochondrial calcium uptake by a H⁺/Ca²⁺ uniporter; (3) removal of calcium via plasma membrane calcium ATPases (PMCA) pumps and the Na⁺/Ca²⁺ exchanger. Plum dotted lines represent calcium influx and release pathways that elevate [Ca²⁺]i. Light blue dashed lines represent calcium-buffering pathways that control increases in [Ca²⁺]i and restoration to resting levels. (B) Model illustrating the hypothesis that advancing age in the absence of pathology, results in a subtle decline in the control of [Ca²⁺]i. Compensation by other control mechanisms may allow neurones to adapt to an age-related decline in control of [Ca²⁺]i. Specifically, this model illustrates the mechanisms that lead to elevated [Ca²⁺]i in aged peripheral adrenergic neurones. The rise in [Ca²⁺]i mediated via calcium influx and release from the SER is buffered by SERCA whose function declines with age (broken red line). In response to the decline in SERCA function mitochondria, PMCA and Na⁺/Ca²⁺ exchanger compensate (thick red solid lines) for the decline in SERCA function by increasing Ca²⁺ uptake and removal so as to preserve overall neuronal viability. In addition, the decline in SERCA function may possibly alter ER Ca²⁺ filling levels, which may have consequences for sustained CICR in senescent neurones.

Fig. 2

Summary of major findings of age-related alterations in the function of peripheral autonomic neurones and [Ca²⁺]i regulation.