WRITER: JENNIFER BROWN
CONTACT: DAVE PEDERSEN
Iowa City IA 52242
(319) 335-8032; fax (319) 384-4638
Release: July 5, 2001
EMBARGOED UNTIL 1 P.M. (CDT) JULY 5, 2001
UI team investigates cell signaling pathway in heart and brain
IOWA CITY, Iowa -- Discoveries by a team of researchers from the University
of Iowa, the University of Wisconsin-Madison and the University of North Carolina
may help scientists solve an important biological question.
"A long-standing puzzle in the cellular signaling field was how a single
cell like a neuron (nerve cells in the brain) can possess a variety of receptors
that use the same signaling pathways but have different effects on the cell,"
said Johannes W. Hell, Ph.D., UI associate professor of pharmacology and principal
investigator on the study. Hell recently moved to the UI from the University
of Wisconsin-Madison where he conducted this work. Several established UI
researchers collaborated with Hell in this study.
The researchers determined that close physical proximity in a cell between
the various proteins involved in the message relay or signaling system, as
well as the biochemical connections between the components, allowed the precise
and specific delivery of a biological signal to its correct destination. The
findings are published in the July 6 issue of the journal Science.
Hell's team investigated a ubiquitous cell biological signaling system whereby
biochemical messages in the human body and brain are converted into cellular
actions that control critical physiological functions, such as the heartbeat.
These systems consist of a receptor molecule, which receives a biochemical
message, and a series of transmitter proteins, which relay the message to
the correct action molecule in the cell. Although the receptor / action molecule
pairs are often highly specific for each other, the transmitter proteins,
which act like wires, connecting these varied partners are often the same
or similar molecules in each case. Determining the mechanisms used by cells
to ensure that these wires don't get crossed and deliver the signal to the
wrong place is an important area of research.
"We discovered that one of the receptors for adrenaline, the beta 2
adrenergic receptor, and all components of the signaling pathway used by this
receptor are associated with a calcium channel known as the L-type channel,"
The team's results showed that all the components of this signaling complex
reside close to each other in the cell and appear to be physically associated
with one another. In addition, the scientists also found that stimulating
this receptor only stimulates the activity of those calcium channels that
are in the immediate vicinity of the receptor.
"Our studies show that signaling by these receptors is localized and
thereby specific, even within a single cell," Hell said. "The signaling
is physically restricted to microdomains in a cell and does not activate other
signaling pathways in other subcellular domains that might lead to a different
Calcium is a critical regulator of cellular functions. It regulates the heartbeat
and the excitability of neurons. Adrenaline binding to its receptor on a heart
cell or neuron causes a signal to go to the calcium channels in the cell membrane
modifying their activity. The channels open, controlling the flow of calcium
into the cell. The results of relaying the message are an elevated heart beat
during the fight-or-flight response and a change in neuronal excitability
in the brain.
Overactivation of calcium channels is responsible for various neurological
disorders including stroke and epilepsy-related brain damage. During aging,
the activity of L-type calcium channels in neurons is increased. Several studies
suggest that this long-term increase in calcium flow into neurons contributes
to neurological damage during aging and especially Alzheimer's disease.
Hell hopes that understanding the regulation of this channel will provide
the scientific basis for developing drugs to control the activity of this
channel in old age and thereby alleviating the symptoms of dementia.
In addition to Hell, the team included Monika A. Davare, Ph.D., Duane D.
Hall, Ph.D., Erik M. Peden, and Mary C. Horne, Ph.D., (now an assistant professor
at the UI), at the University of Wisconsin-Madison. UI researchers included
Toshinori Hoshi, Ph.D., associate professor of physiology and biophysics,
and Vladimir Avdonin, Ph.D. University of North Carolina investigators included
Richard J. Weinberg, Ph.D., research associate professor of cell biology and
anatomy, and Alain Burnette, Ph.D.
The study was funded in part by five different grants from the National Institutes
of Health to Drs. Hell, Horne, Hoshi, and Weinberg, and the American Heart
Association to Drs. Hell and Avdonin. Hell also received funding from a Shaw
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