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Evans Lab Study Published in Nature Communications

The discovery of this cell-wide web reveals for the first time how cells deliver function-specific calcium signals to coordinate the wide diversity of cellular processes that are modulated by this divalent cation.

Cell-wide web

The cell-wide web refers to a cell-wide network of distinct “cytoplasmic nanocourses” with the nucleus at its centre, demarcated by sarcoplasmic reticulum (SR) nanojunctions (≤400 nm across) that restrict calcium diffusion and by nanocourse-specific calcium‑pumps and release channels that facilitate signal segregation. In arterial smooth muscle, for example, relaxation is mediated by unloading SR calcium into peripheral nanocourses delimited by junctional membrane complexes formed between the SR and the plasma membrane, facilitating onward calcium removal from the cell. Conversely, stimulus‑specified increases in SR calcium flux through discrete ion channel clusters selects for rapid propagation of calcium signals throughout deeper extraperinuclear nanocourses and thus myocyte contraction. Nuclear envelope invaginations incorporating a different calcium pumps in their outer nuclear membranes demarcate further diverse networks of cytoplasmic nanotubes that receive calcium signals through further discrete calcium channel clusters, impacting gene expression through epigenetic marks segregated by their associated invaginations.

Nanoscale

Regardless of the functional subdivision of nanocourses, all path lengths from calcium release site to targeted signalling complexes must be on the nanoscale, with picolitre volumes of cytoplasm lying within the boundaries of each nanocourse. Relatively small net increases in local calcium flux (1-2 ions per picolitre) will therefore be sufficient to raise the local concentration into the affinity ranges of most cytoplasmic calcium binding proteins. Calcium binding proteins may thus operate as local “switches” that coordinate nanocourse-specific functions, the probability of moving from OFF to ON determined by changes in unitary rather than macroscopic calcium flux. Significantly, coincident quantum calcium flux can thus be triggered in two distant parts of the cell at the same time, to coordinate, for example, myocyte relaxation and associated gene expression regulation.

Gene expression

Invaginations of the nuclear envelope confer further segregated and diverse networks of cytoplasmic nanocourses that project deep into the nucleoplasm. These invaginations break down themselves into multiple subtypes based on the distribution of histone epigenetic marks on the chromatin underlying the lamina of the inner nuclear membrane. The authors postulate that calcium flux across the outer nuclear membrane into nuclear nanocourses may thus contribute additional levels of genome regulation by, for example, releasing these specific, segregated chromatin types for cycles of reactivation in differentiated cells and providing a path for related gene repression during phenotypic modulation.

Network plasticity and disease

Importantly, this cellular “intranet” conferred by the SR and its associated network activities are not hardwired, reconfiguring to deliver different outputs during phenotypic modulation on the path, for example, to cell proliferation.

Therefore, understanding how this network is organised through the spatial segregation of junctional membrane complexes, and the processes by which it is reconfigured in health and disease, will reveal new therapeutic strategies for diseases such as pulmonary hypertension, neurodegeneration and cancer.

Quantum biology

The way the cell-wide web operates draws obvious parallels to mechanisms of conduction in single-walled carbon nanotubes, which behave as quantum wires that transmit charge carriers through discrete conduction channels, enabling memory, logic and parallel processing. Thus, by analogy, these observations point to the incredible signalling potential that may be afforded by modulating “quantum calcium flux” on the nanoscale, in support of network activities within cells. In short, these findings are an example of quantum biology – an emerging field that uses quantum mechanics and theoretical chemistry to solve biological problems.

The study, published in Nature Communications, was funded by the British Heart Foundation.

 

Prof Mark Evans