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Temple researchers discover key to heart failure, new therapies on horizon
Date:3/5/2013

effectively treat heart failure.

The GRK5 enzyme is a unique member of the GRK family, owing to its presence in the nucleus. Its journey begins at the cell membrane, where signals received by a molecule at the cell surface known as a Gq-coupled receptor prompt "escorts" one of which is calmodulin, as the researchers discovered to attach to GRK5 and guide it to the nucleus.

The team found that GRK5's transport requires calmodulin after examining different places on the enzyme where various escort molecules attach. They then introduced mutations that altered the attachment sites. Only when calmodulin-binding residues on GRK5 were mutated was the enzyme prevented from reaching the nucleus. Those mutations led to dramatic decreases in nuclear GRK5 levels and corresponding declines in the activity of genes known to drive cardiac hypertrophy. Calmodulin's ability to bind to GRK5 is in turn dependent on calcium. The same results were obtained both in vitro, using human heart muscle cells cultivated under laboratory conditions, and in vivo, in mice.

The team's research also marks a breakthrough in scientists' understanding of the role of neurohormones in hypertrophy. Released by specialized neurons into the bloodstream, neurohormones have long been cited as a cause of heart cell enlargement.

"One of the novel findings to fall out of this paper is that not all hypertrophic signals from neurohormones are the same," Koch explained. "That's something to keep in mind as we move forward."

The next step, according to Koch, is to test the ability of different agents to keep GRK5 out of the nucleus. "We are now discussing a trial on inhibition of another cardiac GRK, GRK2," he said. He cautioned, however, that trials in patients with GRK5 inhibition are years away. First, agents capable of blocking GRK5 transport must be identified and tested in animals.

The work is an important advance for Temple's Center for Translational
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Contact: Jeremy Walter
Jeremy.Walter@tuhs.temple.edu
215-707-7882
Temple University Health System
Source:Eurekalert

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