Endoplasmic reticulum calcium tunnels integrate signalling in polarised cells
Introduction
The omnipotence of the Ca2+ signalling system is generally accepted [1]. The involvement of Ca2+ in the regulation of a wide range of cellular reactions has been demonstrated again and again since 1943, when Lewis Heilbrunn contemplated that “the reaction of this calcium with the protoplasm inside the cell is the most basic of all protoplasmic reactions” [1], [2]. Furthermore, Ca2+ signalling cascades are responsible for the execution of numerous cellular death programmes, ranging from the physiological apoptosis to the pathological necrosis [3], [4], [5], [6]. Nevertheless, a full understanding of the detailed behaviour of Ca2+ signalling systems, which allows omnipotence, is still far from having been achieved.
Section snippets
Ca2+ signal propagation
Intracellular propagation of Ca2+ signals is fundamental to the operational versatility of Ca2+ signalling, since local Ca2+ fluctuations generated in a specific sub-cellular compartment regularly need to be conveyed to distant parts of the cell. This task assumes particular importance in highly polarised cells, such as neurons and epithelial units, in which the site of signal initiation often lies far away from the physiological Ca2+ targets. The remarkable compartmentalisation of Ca2+ signals
Properties of the ER membrane
Long-range intracellular Ca2+ signal propagation therefore takes an alternative path, utilising a specific intracellular organelle, the endoplasmic reticulum (ER). The ER, moulded from a multitude of tubules and cysternae serves as an integrating organelle, which fine tunes an extended array of input signals into the synthesis of proteins, their post-translational modification and transport to various parts of the cell [17], [18], [19]. In addition, the ER is capable of generating a variety of
Movement of Ca2+ through the ER lumen
Ca2+ ions can travel through the ER lumen much easier than through the cytosol [33], [35], due to different Ca2+ buffer characteristics in these two compartments. The intra-ER Ca2+ binding proteins have a KD in the range of 0.5–1.0 mM, whereas cytosolic buffers bind Ca2+ with a KD around 50–100 nM. The Ca2+ binding capacity of the ER interior has only been determined indirectly, but – at least in the pancreatic acinar cells – it would appear that it is ∼100 times lower than the Ca2+ binding
Direct demonstration of Ca2+ tunnelling in neurons
Recently the neuronal ER Ca2+ tunnel was discovered experimentally. Using shrewdly designed protocols, Park and his colleagues [41] described internal Ca2+ connectivity between the somatic and dendritic ER in midbrain neurones. Moreover they demonstrated replenishment of a dendritic portion of the ER by Ca2+ entering from an un-stimulated part of the ER and monitored directly Ca2+ transport through the ER lumen from the soma to the dendrites.
These results are of a fundamental importance,
Acknowledgements
Author's research was supported by MRC (OHP), INTAS (AV), Alzheimer Research Trust (AV) and NIH (AV).
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