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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," Hell explained.

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 cellular response."

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 Scientist Award.

University of Iowa Health Care describes the partnership between the UI College of Medicine and the UI Hospitals and Clinics and the patient care, medical education and research programs and services they provide. Visit UI Health Care online at www.uihealthcare.com.