Calcium Kicks

Editor's choice in physiology

By | March 1, 2011

Cell membrane ion channel. Computer artwork of an ion channel (orange) in a lipid bilayer plasma membrane. The ion channel is a pore-forming transmembrane protein that allows selected ions (yellow) to diffuse in and out of the cell. The ions move down their electrochemical gradient changing the electrical potential of the cell. This mechanism is particularly important in nerve and muscle cells, where it is responsible for the transmission of nerve impulses and contraction of fibers respectively. The membrane of the cell consists of a dual layer of phospholipids (green), with the hydrophobic lipid tails in the center and the hydrophilic phosphate groups on either side. Medi-Mation ltd / Photo researchers inc.



The paper

M.D. Fuller et al., “Molecular mechanism of calcium channel regulation in the fight-or-flight response,” Sci Signal, 3:ra70, 2010. Free F1000 Evaluation

The finding

Pounding heart, tight muscles, and rapid breathing are all familiar effects of the “fight or flight” response. Adrenaline receptors turn on protein kinase A (PKA), which opens calcium channels in muscle tissue, tensing the body for action. But which residues PKA phosphorylates to release a stopper mechanism within the channel was a 25-year-old mystery—until William Catterall and colleagues from the University of Washington in Seattle painstakingly worked out the details.

The mystery

The whole field was stumped, says Catterall: “It was an embarrassment we were all sweeping under the rug.” His lab tried to put the complex together in transfected cells, but they couldn’t get it to work. “It was a lot of frustration for multiple people in the lab,” he says.

The key

Then they had the idea to reduce the amount of a critical component. PKA is anchored to the membrane via a protein called AKAP. Catterall and colleagues noticed that too much free AKAP prevented the PKA bound to AKAP from reaching the channel. Once they reduced the amount they were putting into the cells, PKA was able to phosphorylate the channel and release the stopper mechanism.

The disease

Cracking this problem has now made it possible to study the regulation of calcium channels in normal heart function, and to ask if it’s impaired in heart failure. Catterall’s lab has just started doing those experiments. “We’re optimistic we will learn something interesting,” he says.

F1000 evaluators: G. Zamponi (Univ of Calgary)N. Dascal (Tel Aviv Univ)A. Dolphin (Univ Col London)


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