Biological complexity: controlling intercellular signalling (Introduction)

by David Turell @, Tuesday, August 25, 2020, 20:36 (1311 days ago) @ David Turell

The cells have a method of constricting molecular movement to allow proper interpretation:

https://phys.org/news/2020-08-enzyme-prisons-cell-molecule.html

"There are up to a hundred different receptors on the surface of each cell in the human body. The cell uses these receptors to receive extracellular signals, which it then transmits to its interior. Such signals arrive at the cell in various forms, including as sensory perceptions, neurotransmitters like dopamine, or hormones like insulin.

"One of the most important signaling molecules the cell uses to transmit such stimuli to its interior, which then triggers the corresponding signaling pathways, is a small molecule called cAMP. This so-called second messenger was discovered in the 1950s. Until now, experimental observations have assumed that cAMP diffuses freely—i.e., that its concentration is basically the same throughout the cell—and that one signal should therefore encompass the entire cell.

***

"The team now reports in Cell that, contrary to previous assumptions, the majority of cAMP molecules cannot move around freely in the cell, but are actually bound to certain proteins—particularly protein kinases. In addition to the three scientists and Professor Martin Falcke from the MDC, the research project involved other Berlin researchers as well as scientists from Würzburg and Minneapolis.

"'Due to this protein binding, the concentration of free cAMP in the cell is actually very low," says Professor Martin Lohse, who is last author of the study and former head of the group. "This gives the rather slow cAMP-degrading enzymes, the phosphodiesterases (PDEs), enough time to form nanometer-sized compartments around themselves that are almost free of cAMP." The signaling molecule is then regulated separately in each of these tiny compartments. "This enables cells to process different receptor signals simultaneously in many such compartments," explains Lohse. The researchers were able to demonstrate this using the example of the cAMP-dependent protein kinase A (PKA), the activation of which in different compartments required different amounts of cAMP.

***

"The team's measurements showed that most compartments are actually smaller than 10 nanometers—i.e., 10 millionths of a millimeter. This way, the cell is able to create thousands of distinct cellular domains in which it can regulate cAMP separately and thus protect itself from the signaling molecule's unintended effects. "We were able to show that a specific signaling pathway was initially interrupted in a hole that was virtually cAMP-free," said Annibale. "But when we inhibited the PDEs that create these holes, the pathway continued on unobstructed."

"'This means the cell does not act like a single on/off switch, but rather like an entire chip containing thousands of such switches," explains Lohse, summarizing the findings of the research. "The mistake made in past experiments was to use cAMP concentrations that were far too high, thus enabling a large amount of the signaling molecule to diffuse freely in the cell because all binding sites were occupied.'"

Comment: this complex design shows how molecules are carefully controlled to avoid error and create clear signals.


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