Key to Heart Failure, Path to New Treatments
Discovered by Temple Researchers
First to show that an enzyme called GRK5 (G-protein
coupled receptor kinase 5) can gain access to a heart cell's command
center, where control of its genes is maintained
March 7, 2013 - Some 5.8 million Americans suffer
from heart failure, a currently incurable disease. But scientists at
Temple University School of Medicine's (TUSM) Center for Translational
Medicine have discovered a key biochemical step underlying the condition
that could aid the development of new drugs to treat and possibly
"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.
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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,
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
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
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
Temple Health refers to the health, education and
research activities carried out by the affiliates of Temple University
Health System and by Temple University School of Medicine.
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