Inseparable tandem: evolution chooses ATP and Ca2+ to control life, death and cellular signalling

Abstract

From the very dawn of biological evolution, ATP was selected as a multipurpose energy-storing molecule. Metabolism of ATP required intracellular free Ca(2+) to be set at exceedingly low concentrations, which in turn provided the background for the role of Ca(2+) as a universal signalling molecule. The early-eukaryote life forms also evolved functional compartmentalization and vesicle trafficking, which used Ca(2+) as a universal signalling ion; similarly, Ca(2+) is needed for regulation of ciliary and flagellar beat, amoeboid movement, intracellular transport, as well as of numerous metabolic processes. Thus, during evolution, exploitation of atmospheric oxygen and increasingly efficient ATP production via oxidative phosphorylation by bacterial endosymbionts were a first step for the emergence of complex eukaryotic cells. Simultaneously, Ca(2+) started to be exploited for short-range signalling, despite restrictions by the preset phosphate-based energy metabolism, when both phosphates and Ca(2+) interfere with each other because of the low solubility of calcium phosphates. The need to keep cytosolic Ca(2+) low forced cells to restrict Ca(2+) signals in space and time and to develop energetically favourable Ca(2+) signalling and Ca(2+) microdomains. These steps in tandem dominated further evolution. The ATP molecule (often released by Ca(2+)-regulated exocytosis) rapidly grew to be the universal chemical messenger for intercellular communication; ATP effects are mediated by an extended family of purinoceptors often linked to Ca(2+) signalling. Similar to atmospheric oxygen, Ca(2+) must have been reverted from a deleterious agent to a most useful (intra- and extracellular) signalling molecule. Invention of intracellular trafficking further increased the role for Ca(2+) homeostasis that became critical for regulation of cell survival and cell death. Several mutually interdependent effects of Ca(2+) and ATP have been exploited in evolution, thus turning an originally unholy alliance into a fascinating success story.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'.

Keywords: ATP; ATP receptors; Ca2+; calcium; evolution; intracellular organelles.

Figure 1.

Regulatory principles in Ca²⁺-based signalling and ATP-based energetics. As [Ca²⁺]_o is much higher than [Ca²⁺]_i, Ca²⁺ steadily leaks into the cell (not drawn), but this is counterbalanced by the Ca²⁺–ATPase/pump and by antiporters. Upon stimulation, Ca²⁺ can flow into the cell by influx channels of different types. Rapid downregulation is executed by Ca²⁺-binding proteins (CaBP) and by sequestration mainly into the endoplasmic reticulum (endowed with an organellar Ca²⁺-pump), but also into other organelles, such as cortical stores, the Golgi apparatus, different trafficking organelles and mitochondria. In their inner membrane, mitochondria have available a uniporter for Ca²⁺ uptake and a antiporter system for its rapid release. Ca²⁺-release channels, mainly of the type InsP₃R and RyR, are available in the different organelles. In the endophago/lysosomal trafficking system, such channels can mediate short-range Ca²⁺ signalling. Requirement of Ca²⁺ is also ascertained for stimulated exocytosis, whereby Ca²⁺ may originate from influx and/or release from cortical stores. Regulation of apoptosis (regulated cell death), among a plethora of molecules, involves release of Ca²⁺ from the endoplasmic reticulum and release of an ‘apoptosis-inducing factor’ as well as of cytochrome c from mitochondria. In summary, in the eukaryotic cell, there are many local signalling pathways, with many interactions, for a variety of subcellular processes.