Acidic calcium stores open for business: expanding the potential for intracellular Ca2+ signaling

Abstract

Changes in cytosolic calcium concentration are crucial for a variety of cellular processes in all cells. It has long been appreciated that calcium is stored and released from intracellular calcium stores such as the endoplasmic reticulum. However, emerging evidence indicates that calcium is also dynamically regulated by a seemingly disparate collection of acidic organelles. In this paper, we review the defining features of these 'acidic calcium stores' and highlight recent progress in understanding the mechanisms of uptake and release of calcium from these stores. We also examine the nature of calcium buffering within the stores, and summarize the physiological and pathophysiological significance of these ubiquitous organelles in calcium signaling.

Figure 1. The acidic calcium stores

Schematic representation of acidic organelles that contain high concentrations of calcium.

Figure 2. Acidocalcisomes in whole cells and subcellular fractions

(a), (b), ultrathin sections of Agrobacterium tumefaciens (a) or Trypanosoma brucei procyclic forms (b) showing the acidocalcisomes as empty vesicles with electron-dense inclusions (arrows). (c), (d), visualization of acidocalcisomes in whole unfixed Herpetomonas anglusteri and Trypanosoma cruzi acidocalcisome fraction obtained by iodixanol centrifugation [6] allowed to adhere to Formvar- and carbon-coated grids and then observed by direct transmission electron microscopy (using an energy filter in (c)).Acidocalcisomes (black granules) appear disperse in the cytoplasm (c) or fraction (d). Scale bars: (a), 0.2 μm; (b), 2 μm; (c), 0.5 μm; (d), 1 μm. (a) was taken by Manfredo Seufferheld. (c) is reproduced with permission from ref. [114].

Figure 3. Lysosomal calcium stores in neurons

Top, Schematic representation of a cell depicting high levels of calcium on the outside of the cell (red), within endoplasmic reticulum calcium stores (blue) and within lysosomal calcium stores (green). The concentration of free calcium in these compartments ([Ca²⁺]_free) is listed. The bottom panel shows measurements of cytosolic calcium levels in hippocampal neurons upon depolarization with high K⁺ (to stimulate calcium influx from the extracellular space). The cells were then sequentially stimulated (in the absence of external calcium) with thapsigargin (to stimulate depletion of ER calcium stores) and GPN (to lyse lysosomal calcium stores). All three maneuvers raise the cytosolic calcium concentration. The data in the bottom panel was obtained by George Dickinson.

Box 1 Figure I. Calcium transport in to acidic calcium stores

Schematic of an acidic calcium store depicting calcium pumps and exchangers that mediate calcium uptake (top) and V-ATPases and V-PPases responsible for acidification (bottom).

Box 2 Figure II. Calcium release from acidic calcium stores

Schematic of an acidic calcium store depicting calcium-permeable channels (top) which mediate calcium release (top) and V-ATPases and V-PPases responsible for acidification (bottom).

Box 3 Figure III. NAADP-mediated channel “chatter”

Schematic showing proposed mechanism of action of NAADP starting with the generation of a local calcium signal from an acidic calcium store and subsequent amplification by the ER resulting in a global calcium signal.