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Until now, the only known way to turn on a G-protein was via a
receptor sitting on a cell�s surface membrane. This receptor acts like
a telegraph operator, accepting outside signals and relaying them
inside the cell. It converts an external signal, like caffeine, into
action � in this case, a nerve signal to the brain.
More than half of all drugs, from asthma and heart medicine to
antidepressants, target G-protein receptors. Discovering a protein
that activates G-proteins from inside a cell could open up an entirely
new pathway for drug development, said Henrik Dohlman, Ph.D., senior
study author and a professor of biochemistry and biophysics in UNC�s
School of Medicine.
�No drug is 100 percent effective, 100 percent free of side effects
and 100 percent safe. The more options we have biochemically, the more
selective we can be in designing new drugs. If we can find another way
of modulating G-proteins, we could expand the drug targets that are
available to pharmacology,� Dohlman said.
The study appeared online Feb.7, 2008, in the journal Current Biology
and will be published in the Feb. 14, 2008, print edition. Funding was
provided by the National Institutes of Health and a UNC Cell and
Molecular Biology Program predoctoral fellowship.
Despite 20 years of study, G-protein signaling continues to produce
surprises. The advent of the human genome project revealed that some
three percent of our DNA is dedicated to these messenger molecules.
However, the genomic data also drew biologists away from the research
technique the UNC team used to discover the new protein, Dohlman said.
�People stopped looking for things that could activate G-proteins
using functional criteria,� he said. Instead, they searched for new
receptors and activators based on common genetic patterns.
Mike Lee, a graduate student in the UNC School of Medicine�s
department of pharmacology, identified the new protein, called Arr4,
in yeast cells. Lee employed a mutant form of G-protein to search for
any messengers inside the yeast cell with an affinity for G-proteins.
�We went looking for things that could activate G-proteins but don�t
resemble known receptors,� Lee said.
He identified seven proteins that weren�t receptors, but did bind to
G-proteins, and did further tests on one of the seven proteins, Arr4,
to determine its function.
In yeast, Arr4 is involved in cell fusion, a process in which two
yeasts fuse together to form one cell, combining their genetic data. A
G-protein coupled receptor (GPCR) controls cell fusion, while Arr4
appears to play a supporting role.
Lee said he thinks that Arr4 may allow the cell to go through several
additional rounds of signal activation without needing to go back to
the receptor.
�Our current thinking is it�s not so much that this is the ignition
for signaling, it�s more like an overdrive. Once the pathway is
activated by the hormone outside, Arr4 sustains the activity inside,�
Lee said. �What we don�t know is if Arr4 is itself simulated by some
signal, and of course we�re very interested in finding out if that�s
the case.�
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