Article Title: beta-arrestins and cell
signaling
Authors: DeWire, SM;Ahn,
S;Lefkowitz,
RJ;Shenoy, SK
Journal: ANNU REV PHYSIOL
Volume: 69
Issue:
Page: :483-510
Year: 2007
* Duke Univ, Med Ctr, Howard Hughes Med Inst, Durham, NC
27710 USA.
* Duke Univ, Med Ctr, Howard Hughes Med Inst, Durham, NC
27710
(addresses have been truncated)
Why do you think your paper is highly
cited?
The discovery that beta-arrestins could serve as signaling molecules in
their own right, in addition to their classical desensitizing functions,
changed the paradigm for understanding how G protein-coupled receptors
signal and are regulated. The field has grown rapidly over the past 10
years. This review article summarized and synthesized developments in this
field with an emphasis on recent papers demonstrating how the newly
discovered signaling pathways regulated physiology in vivo.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
The paper summarizes and synthesizes knowledge in a rapidly expanding field
of research, namely that of beta-arrestin mediated signaling.
Would you summarize the significance of your paper
in layman's terms?
"I think that
research in this field will
lead to a much deeper
understanding of how the
receptors work and are
regulated..."
Receptors are molecules on or in cells which bind to drugs and hormones,
thus allowing them to initiate their effects on cellular physiology. The
largest class of receptors is called G protein-coupled receptors. This
large family of receptors containing almost a thousand members contains
receptors for such commonly used drugs as "beta blockers," angiotensin
receptor blockers (ARBs), antihistamines, and anti-platelet drugs such as
clopidogrel, to name but a few.
The receptors are termed G protein-coupled receptors (GPCRs), because their
actions have been thought for many years to be mediated solely through a
type of protein called G proteins. Several years ago we discovered that
there was an entirely different mechanism by which the receptors could work
by using a molecule called beta-arrestin, which we had previously
discovered because it actually turns off G protein-mediated signaling.
This discovery has led to a completely new understanding or paradigm for
how the receptors work, which has important implications for drug
discovery. This is important because GPCRs are the most important target of
therapeutic drugs.
How did you become involved in this research, and
were there any problems along the way?
This is a very long story because we discovered the beta arrestins 15-20
years ago. We discovered them as molecules which turned off or desensitized
G protein-mediated signaling by the receptors. It was about 10 years later
that we discovered their ability to actually serve as signaling molecules
in their own right.
As with most new ideas, initially there did not seem to be great enthusiasm
for this discovery. However, in recent years it has been widely accepted
and now there are hundreds of papers on the subject. It is very difficult
to change a scientific paradigm once it is well established.
Where do you see your research leading in the
future?
At a basic science level, I think that research in this field will lead to
a much deeper understanding of how the receptors work and are regulated.
Whole new pathways and networks will be uncovered which are activated
through the beta-arrestin molecules.
I think we have just scratched the surface in terms of their various
functions. Another very important ramification of the work will hopefully
come from the development of novel drugs, which are able to specifically
target these newly discovered pathways leading to novel therapeutic effects
and perhaps more limited side effects.
Robert J. Lefkowitz, M.D.
James B. Duke Professor of Medicine
Investigator, Howard Hughes Medical Institute
Duke University Medical Center
Durham, NC, USA