The remembrance of the things past: Conserved signalling pathways link protozoa to mammalian nervous system

The aim of the present article is to analyse the evolutionary links between protozoa and neuronal and neurosecretory cells. To this effect we employ functional and topological data available for ciliates, in particular for Paramecium. Of note, much less data are available for choanoflagellates, the progenitors of metazoans, which currently are in the focus of metazoan genomic data mining. Key molecular players are found from the base to the highest levels of eukaryote evolution, including neurones and neurosecretory cells. Several common fundamental mechanisms, such as SNARE proteins and assembly of exocytosis sites, GTPases, Ca²⁺-sensors, voltage-gated Ca²⁺-influx channels and their inhibition by the forming Ca²⁺/calmodulin complex are conserved, albeit with different subcellular channel localisation, from protozoans to man. Similarly, Ca²⁺-release channels represented by InsP₃ receptors and putative precursors of ryanodine receptors, which all emerged in protozoa, serve for focal intracellular Ca²⁺ signalling from ciliates to mammalian neuronal cells, eventually in conjunction with store-operated Ca²⁺-influx. Restriction of Ca²⁺ signals by high capacity/low affinity Ca²⁺-binding proteins is maintained throughout the evolutionary tree although the proteins involved differ between the taxa. Phosphatase 2B/calcineurin appears to be involved in signalling and in membrane recycling throughout evolution. Most impressive example of evolutionary conservation is the sub-second dynamics of exocytosis-endocytosis coupling in Paramecium cells, with similar kinetics in neuronal and neurosecretory systems. Numerous cell surface receptors and channels that emerge in protozoa operate in the human nervous system, whereas a variety of cell adhesion molecules are newly "invented" during evolution, enabled by an increase in gene numbers, alternative splice forms and transcription factors. Thereby, important regulatory and signalling molecules are retained as a protozoan heritage.