Brain complexity: synapse signal controls found (Introduction)

by David Turell , Friday, March 08, 2019, 21:22 (1877 days ago) @ David Turell

A feedback loop mechanism is found:

https://medicalxpress.com/news/2019-03-scientists-brain.

"The release of neurotransmitters and hormones in the body is tightly controlled by complex protein machinery embedded in cell membranes.

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"pharmacologist Heidi Hamm, Ph.D., and her colleagues reported the first animal model of an important feedback mechanism, essentially a "shut-off valve" for neurotransmitter and hormone release through SNARE complex-mediated membrane fusion.

"In a paper featured on the cover of the journal Science Signaling, the researchers reported that when they disabled the shut-off valve in nerve cells in the brains of mice through genetic manipulations, the animals exhibited significant deficits in motor coordination, cognitive and other behaviors.

"During her career she has made several important discoveries about G-protein coupled receptors (GPCRs). Embedded in the membranes of nearly every cell, GPCRs are the most common conduit for signaling pathways found in nature. Two-thirds of all drugs target them.

"GPCRs are turned on and off by G-proteins inside the cell. G proteins consist of two subunits—alpha and beta/gamma—both of which can stimulate independent signaling pathways.

"Several years ago, Hamm and colleagues including Simon Alford, Ph.D., at the University of Illinois at Chicago, showed how the beta/gamma subunit of an inhibitory G protein prevents intracellular vesicles containing neurotransmitters from fusing to the cell membrane and spilling their contents into the extracellular space between nerve cells—the synapse.

"It does this in two ways: by preventing the flow of calcium through "calcium channels" from allowing vesicles to fuse to the membrane and by "switching off" the SNARE receptor complex.

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"Using a genome editing technology called CRISPR/Cas9, Zack Zurawski, then a graduate student in Hamm's lab, introduced a mutation that didn't let the beta-gamma subunit turn off the SNARE machinery anymore. The mutation turned on the "spigot."

"'It's amazing that it worked the first time," Hamm said. "It used to take two or three years to make such a mouse and we did it in three months. It was really a great achievement."

"Zurawski, the first author on the paper, has since earned his Ph.D. and is conducting post-doctoral research at the University of Illinois with Alford, a senior co-author.

"The researchers also discovered that the two mechanisms for preventing vesicle fusion, one that acts on calcium channels and the other on SNARE, are synergistic. Blocking both results in a more powerful inhibition of neurotransmitter release than blocking one or the other separately."

Comment: this is standard operating procedure. Feedback loops control most everything. Feedback loops MUST be designed into use all at once. They cannot be made stepwise by hunt and peck chance.