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Rodbell 239 (2): 375
Rodbell et al. 246 (6): 1877
J. Biol. Chem., Vol. 281, Issue 30, 24, July 28, 2006
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Classics
The Effects of Insulin on Fat Cells and the Role of Guanyl Nucleotides in Signal Transduction: the Work of Martin Rodbell
Metabolism of Isolated Fat Cells. I. Effects of Hormones on Glucose Metabolism and Lipolysis
(Rodbell, M. (1964) J. Biol. Chem. 239, 375–380)
The Glucagon-sensitive Adenyl Cyclase System in Plasma Membranes of Rat Liver. V. An Obligatory Role of Guanyl Nucleotides in Glucagon Action
(Rodbell, M., Birnbaumer, L., Pohl, S. L., and Krans, H. M. J. (1971) J. Biol. Chem. 246, 1877–1882)
Martin Rodbell (1925–1998) was born in Baltimore, Maryland. He entered Johns Hopkins University in 1943 but was drafted into the Navy a year later to function as a radio operator attached to the Marine Corps. When he returned from the war in 1946, Rodbell re-entered Johns Hopkins and focused on French literature. Although his father wanted him to go to medical school, Rodbell was not interested because of the intense competition among these students to get the highest grade. A turning point came when Rodbell took a small biology class given by graduate student James Ebert. Ebert's enthusiasm for biology was infectious, and Rodbell began to consider a career in the biological sciences. On the advice of Bentley Glass, he chose biochemistry and spent his first postgraduate year taking every advanced course in chemistry available at Johns Hopkins.
In 1950, Rodbell entered the Ph.D. program in biochemistry at the University of Washington in Seattle. Studying with Donald H. Hanahan, he completed his dissertation titled "Some Aspects of Lecithin Metabolism in the Liver" in 1954. Unfortunately for him, Eugene Kennedy was working on the same subject and succeeded in demonstrating that CTP rather than ATP, as Rodbell had believed, is responsible for the biosynthetic pathway.
After receiving his Ph.D., Rodbell left Seattle for Urbana, Illinois where he became a postdoctoral fellow under Herbert E. Carter and worked on the biosynthesis of the antibiotic chloramphenicol. In 1956 he became a research biochemist in the laboratory of Christian Anfinsen at the National Heart Institute of the National Institutes of Health (NIH) in Bethesda, Maryland. Anfinsen was the author of a previous Journal of Biological Chemistry (JBC) Classic (1). At the NIH, Rodbell continued his research on fats, working on lipoprotein lipase.
In 1961, Rodbell accepted a position in the Laboratory of Nutrition and Endocrinology in the Institute of Arthritis and Metabolic Diseases (NIAMD). He soon became interested in discerning whether lipoprotein lipase was synthesized and released from fat cells. After months of trying to disrupt adipose tissue, Rodbell discovered that collagenase rapidly digested the tissue matrix, releasing the fat cells. The cells then floated to the surface of the incubation medium, making it easy to separate and purify them. Using these fat cells, Rodbell showed that insulin bound directly to receptors on the cells and stimulated glucose metabolism. In 1964, he published the results of these experiments in the first JBC Classic reprinted here. This article became one of the most influential articles in endocrinology of the 1960s and 1970s and has been cited over 1485 times since 1964. Prior to the publication of this article, the actions of insulin had been observed in intact tissues only.
After his article was published, Rodbell became committed to investigating the molecular basis of hormone action on cell surface receptors. In the mid-sixties, he attended a lecture by JBC Classic author Earl Sutherland (2) on his "second messenger" theory of hormone action. In the talk Sutherland postulated that rather than entering a cell, hormones worked at the cell surface and triggered the production of cyclic AMP by adenyl cyclase, which in turn executed the command initiated by the hormones. Rodbell, like many young biochemists in the 1960s, was deeply influenced by the work of Sutherland. As a result of this lecture, his interests shifted from insulin to hormones known to stimulate the production of cyclic AMP in fat cells.
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After a conversation with Oscar H. Hechter, the steroid biochemist whose theories about hormone signaling influenced Earl W. Sutherland's second messenger theory, Rodbell developed his theory of signal transduction. Rodbell believed that the fundamental information processing systems of both computers and biological organisms were similar. Thus, cells contained discriminators, transducers, and amplifiers (otherwise known as effectors). The discriminator, or cell receptor, received information from outside the cell, the transducer processed the information across the cell membrane, and the amplifier (adenylate cyclase) intensified the signals with cyclic AMP to initiate reactions within the cell.
Rodbell realized that his transducer concept needed more fleshing out and set about proving its existence. Using the glucagon-sensitive adenylate cyclase system in liver, he and his colleagues labeled glucagon with 125I to investigate the nature of the glucagon receptor and the relationship between hormone binding and hormonal activation of adenylate cyclase. They discovered that guanyl nucleotides, at extremely low concentrations, altered the binding of 125I-glucagon, suggesting that the nucleotides regulated glucagon binding by an allosteric type of action.
These results raised the question of how GTP affects adenylate cyclase activity, which is the subject of the second JBC Classic reprinted here. Rodbell's initial studies were unsuccessful as rapid hydrolysis of ATP, the substrate for adenyl cyclase, created difficulties in interpreting the kinetic data. To avoid this problem, Rodbell and his colleagues used [
-32P]AMP-PNP, an analogue of ATP containing nitrogen substituted for oxygen between the terminal phosphates. The analogue was resistant to hydrolysis by ATPases in liver membranes and was able to function as an adenyl cyclase substrate. Under these conditions, they discovered that GTP enhanced the rate of glucagon-stimulated adenyl cyclase activity. This led to their conclusion that "guanyl nucleotides play a specific and obligatory role in the activation of adenyl cyclase by glucagon. The nucleotides bind at sites, distinct from the glucagon binding sites, that appear to regulate the response of adenyl cyclase to glucagon."
As a result of these experiments, Rodbell became convinced that a GTP-activated transducer existed and that it mediated the transfer of information between the receptor and the enzyme. It later came to light that the transducer hydrolyzed GTP and that this hydrolysis converted the transducer to its inhibitory state. Alfred G. Gilman decided to determine the chemical nature of Rodbell's transducer. This was the subject of a previous JBC Classic (3). After many years of work, Gilman and his collaborators discovered and eventually purified the first G-protein. Rodbell shared the 1994 Nobel Prize in Physiology or Medicine with Alfred G. Gilman, "for their discovery of G-proteins and the role of these proteins in signal transduction in cells."
Throughout the rest of his scientific career, Rodbell continued to work on G-proteins. From 1968 to 1975 he was the chief of the section on membrane regulation at the NIAMD. He then served as the chief of the Laboratory of Nutrition and Endocrinology at the NIAMD (1975–1985), while working as a visiting professor in the department of clinical biochemistry at the University of Geneva (1981–1983). In 1985 Rodbell moved to North Carolina, where he was the scientific director of the National Institute of Environmental Health Sciences (1985–1989) and the chief of its section on signal transduction (1989–1994), at which time he became scientist emeritus.
In addition to the Nobel Prize, Rodbell received the NIH Distinguished Service Award in 1973 and the Gairdner Award in 1984 and was elected to the National Academy of Sciences in 1987. He was also given several awards and honorary degrees from an international array of institutions including Baltimore City College, the Cleveland Clinic Educational Foundation, the Japanese Biochemical Society, The Johns Hopkins University, Sigma Xi, the University of Geneva, the University of North Carolina School of Medicine, and Virginia Commonwealth University.1
FOOTNOTES
1 All biographical information on Martin Rodbell was taken from Refs. 4 and 5. 
REFERENCES
- JBC Classics: Haber, E., and Anfinsen, C. B. (1962) J. Biol. Chem. 237, 1839–1844 (http://www.jbc.org/cgi/content/full/281/14/e11)
- JBC Classics: Rall, T. W., and Sutherland, E. W. (1958) J. Biol. Chem. 232, 1065–1076; Sutherland, E. W., and Rall, T. W. (1958) J. Biol. Chem. 232, 1077–1092 (http://www.jbc.org/cgi/content/full/280/42/e39)
- JBC Classics: Ross, E. M., and Gilman, A. G. (1977) J. Biol. Chem. 252, 6966–6969; Ross, E. M., Howlett, A. C., Ferguson, K. M., and Gilman, A. G. (1978) J. Biol. Chem. 253, 6401–6412 (http://www.jbc.org/cgi/content/full/280/44/e41)
- Rodbell, M. (1997) Signal transduction: evolution of an idea. In Nobel Lectures, Chemistry 1991–1995 (Ringertz, N., ed) World Scientific Publishing Co., Singapore
- Rodbell, M. (1995) Martin Rodbell—Biography. In The Nobel Prizes 1994 (Frängsmyr, T., ed) Nobel Foundation, Stockholm
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