"Drugs we currently use for heart failure are not very effective," explained lead investigator Walter J. Koch, PhD, Professor and Chairman of the Department of Pharmacology at TUSM, and Director of the Center for Translational Medicine at TUSM. But, he added, "The more we learn about the disease mechanism, the more drug targets we'll find."
That is what Koch and colleagues at Thomas Jefferson University and the University of California, Davis, achieved in their latest study, which appears in the March 5 issue of the online journal PLOS ONE. The report is the first to show that an enzyme called GRK5 (G-protein coupled receptor kinase 5) can gain access to a heart cell's nucleus – its command center, where control of its genes is maintained – by way of a transport mechanism involving calcium and a protein known as calmodulin. Once calcium and calmodulin deliver GRK5 to the nucleus, the enzyme usurps control over specific genes, ultimately causing hypertrophy, in which heart cells grow larger in size. Hypertrophy is a biological hallmark of heart failure.
GRK5 had previously been identified as a key player in maladaptive cardiac hypertrophy, which is the end stage of heart failure, when the heart muscle becomes enlarged and unable to pump enough blood to keep vital organs functioning. While GRK5's ability to get inside the nucleus was known, Koch and colleagues worked to fill in the missing links in its transport mechanism. Those links, they hope, will not only allow them to better understand GRK5's role in causing heart cells to increase in size but also find ways to block that process to more 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 Medicine. GRK5 enters the pipeline of novel drug targets under investigation by the Center's scientists and clinicians, who share the common goal of coordinating clinical practice and basic research to speed the delivery of new therapies to patients.
"It's another entry into larger, pre-clinical animal studies," Koch said. "Something new to start down the path of translational medicine."
Other researchers contributing to the work include Jessica I. Gold, Jeffrey S. Martini, and Jonathan Hullmann at the Center for Translational Medicine at Thomas Jefferson University; Erhe Gao, J. Kurt Chuprun, Douglas G. Tilley, and Joseph E. Rabinowitz at TUSM; and Julie Bossuyt and Donald M. Bers at the University of California, Davis.
The research was supported by NIH grants P01 HL091799 and P01 HL075443 and by a pre-doctoral Fellowship from the Great Rivers Affiliate of the American Heart Association.About Temple Health
Jeremy Walter | EurekAlert!
Researchers release the brakes on the immune system
18.10.2017 | Rheinische Friedrich-Wilhelms-Universität Bonn
Norovirus evades immune system by hiding out in rare gut cells
12.10.2017 | University of Pennsylvania School of Medicine
University of Maryland researchers contribute to historic detection of gravitational waves and light created by event
On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.
It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...
17.10.2017 | Event News
10.10.2017 | Event News
10.10.2017 | Event News
20.10.2017 | Information Technology
20.10.2017 | Materials Sciences
20.10.2017 | Interdisciplinary Research