Environmental Factor, June 2008, National Institute of Environmental Health Sciences
Duke-HHMI Researcher Delivers Rodbell Lecture
By Robin Arnette
It has been nearly a decade since Martin Rodbell, Ph.D., NIEHS Scientific Director from 1985-1989, delivered his last lecture at the Institute in November 1998. Since then the lecture series that bears his name has brought a number of prominent researchers to NIEHS to discuss their work and distinguished careers in science. On May 5 Robert J. Lefkowitz, M.D., became the tenth speaker to give the Dr. Martin Rodbell Lecture Series seminar in Rodbell Auditorium. The talk was titled "Seven Transmembrane Receptors," and David Armstrong, Ph.D., acting chief of the Laboratory of Neurobiology, hosted the event.
Lefkowitz(http://www.biochem.duke.edu/robert-j-lefkowitz-secondary) , the James B. Duke Professor of Medicine and Biochemistry at Duke University Medical School, is also an investigator with the Howard Hughes Medical Institute (HHMI), an appointment he received in 1976. He was also elected to the National Academy of Sciences in 1988.
Lefkowitz began his talk with reflections on one of his mentors. "I consider myself fortunate that I began my own research career in 1968 in Building 10 of the NIH where there was tremendous intellectual ferment," he said. "A number of the real giants of modern biomedical research were plying their trade, none more important than Marty Rodbell."
After paying homage to Rodbell, Lefkowitz divided his discussion into three parts: a brief historical perspective on seven transmembrane receptors, current research efforts on the function and regulation of these receptors, and the possible development of a new therapeutic.
Work from many different labs has determined that seven transmembrane receptors, also known as G protein-coupled receptors, are the largest, most versatile and ubiquitous of the several families of plasma membrane receptors. They are involved in a variety of physiological processes in mammals including the sense of taste and smell. However, it wasn't until the 1970s that researchers could even study these receptors on the molecular level.
Lefkowitz admitted that when he started his career, there was still a lot of skepticism within the scientific community as to whether these receptors existed, so he and his collaborators developed a new technology called radioligand binding to study them. Lefkowitz used the technique to examine the ?-adrenergic receptor and discovered a variety of receptor subtypes. "We were able to document that the receptors were not static entities; their numbers could vary dramatically under various pathophysiological circumstances," he said.
In 1986 he cloned and sequenced the ?2-adrenergic receptor. The results signaled the beginning of a new era in receptor research. Lefkowitz said, "It surprised us and everybody else in the signaling community because it contained all of the characteristics of what we know today as G protein-coupled receptors: seven membrane spans, sites for glycosylation at the amino terminus and sites for regulatory phosphorylation in the cytoplasm." Most strikingly it was homologous with rhodopsin, a chromoprotein contained in the light-sensitive rod cells in the retina of the eye.
The Lefkowitz lab currently focuses on understanding the complexities behind the activation and desensitization of these receptors. When a G protein-coupled receptor is activated, it stimulates G proteins. Often second messenger kinases are stimulated to produce a cellular response. Furthermore, the activated form of the receptor is recognized and phosphorylated by a small family of regulatory kinases called G protein-coupled receptor kinases (GRKs). ?-arrestins, a second family of proteins, bind and sterically interdict further signaling of the G protein, a process known as desensitization. Research has determined that the ?-arrestin/GRK system also serves as a signaling intermediate involved in the activation of a growing list of biochemical signaling pathways including cell survival and anti-apoptosis, chemotaxis, dopaminergic behaviors and cardiac contractilities to name a few. Because ?-arrestins are able to scaffold together several members of an individual pathway, Lefkowitz believes it may be the key to the treatment of disease.
"Biosensors have determined that distinct conformations of ?-arrestin correspond to distinct conformations of the receptor, and these are associated with distinct functions," he explained. "We think this may provide the basis for a new type of therapeutic."