Signal Transduction and the Discovery of G-Proteins, 1969-1980

"Signal transduction" describes how individual cells receive, process, and ultimately transmit information derived from external "signals," such as hormones, drugs, or even light. Martin Rodbell applied the phrase to molecular biology in November 1969 after conversations with Oscar Hechter, the steroid biochemist whose theories about hormone signaling influenced Earl W. Sutherland's "second messenger" concept in the 1950s. Rodbell's and Hechter's use of the term "signal transduction" also can be traced to the influence of information theory and cybernetic science on a growing cadre of post-World War II mathematicians, chemists, computer experts, and biologists, including Edwin Jaynes, Joshua Lederberg, Norbert Wiener, and Hubert Yockey.

Employing signal transduction theory, Rodbell believed that the fundamental information processing systems of both computers and biological organisms were similar. Using the analogy of the "transducer," he asserted that individual cells were cybernetic systems made up of three distinct molecular components: discriminators, transducers, and amplifiers (otherwise known as effectors). The discriminator, or cell receptor, receives information from outside the cell; a cell transducer processes this information across the cell membrane; and the amplifier intensifies these signals to initiate reactions within the cell or to transmit information to other cells.

In December 1969 and early January 1970, Rodbell was working with a laboratory team that studied the effect of the hormone glucagon on a rat liver membrane receptor--the cellular discriminator that receives outside signals. In order to try to reverse the binding of glucagon to the cell membrane, Rodbell and his colleagues introduced ATP (adenosine triphosphate), a nucleotide that is a major source of cellular energy as well as a primary component of ribonucleic acid (RNA). Rodbell discovered that ATP could reverse the binding action of glucagon to the cell receptor and thus dissociate the glucagon from the cell altogether.

Rodbell then compared a number of other nucleotides to see how they dissociated glucagon from the cell. He noted that, in his experiments with ATP, traces of GTP (guanosine triphosphate) were effective at one-thousandth the concentration of the sample of ATP they were using. In other words, GTP could reverse the binding process almost one thousand times faster than ATP. Rodbell deduced that GTP was probably the active biological factor in dissociating glucagon from the cell's receptor, and that GTP had been present as an impurity in his earlier experiments with ATP. The comparative differences between ATP and GTP, and the potency of GTP by itself, can be seen clearly by viewing the original graphs made by Rodbell in those early laboratory experiments. The full results of these experiments were published in a now-classic series of five articles in the Journal of Biological Chemistry in 1971.

By 1972, Rodbell argued that GTP had a profound effect on the ability of a receptor to transmit information across the membrane. He observed that, as GTP promoted the release of bound glucagon, so the act of binding glucagon to the cell membrane promoted the formation of GTP. This GTP, he found, stimulated the activity in the guanine nucleotide protein (later called the G-protein) in the cell. That protein in its active form in turn produced profound metabolic effects in the cell. This activation of the G-protein, Rodbell postulated, was the "second messenger" process Sutherland had described. In the language of signal transduction, the G-protein was the crucial link between the discriminator and the amplifier that transmitted information throughout the membrane. The G-protein, activated by GTP, was the principal component of the transducer.

Still, Rodbell did not understand exactly how GTP stimulated the G-protein, or how it made signal transduction possible. (The biochemical structure of this process would be explained later by Alfred Gilman.) Furthermore, it was still unclear whether or not the "GTP effect" he had discovered was specific only to rat liver membranes, or if it demonstrated a universal principle of cellular activity.

In 1973, Rodbell and several colleagues had a synthetic analog of GTP manufactured that would not break down under normal metabolic processes. In all of the cells Rodbell's team tested, the synthesized GTP by itself stimulated the G-protein. The results of this work were published in Proceedings of the National Academy of Sciences in 1974. Rodbell's discovery of the "GTP effect" sparked a revolution in molecular biochemistry, since any scientist could now obtain this synthetic GTP and activate a cell's G-protein transducer in his or her own laboratory.

Rodbell's further research proved that cellular communication was far more complex and unpredictable than anyone had previously understood. By 1976, Rodbell indicated that the G-protein not only could process (or transduce) hormone signaling across the membrane, but that it could also inhibit signaling at the discriminator point. Rodbell postulated, and then provided evidence for, additional G-proteins at the cell receptor that could inhibit and activate transduction, often at the same time. In other words, cellular receptors were sophisticated enough to have several different processes going on simultaneously. Rodbell presented this more subtle understanding of the potential of G-proteins to carry out primary and secondary processes of signal transduction in the Journal of Biological Chemistry in 1977 and 1979.

A broad outline of Rodbell's ten-year work with G-proteins (1969-1979) was published in Nature in 1980, "The Role of Hormone Receptors and GTP-Regulatory Proteins in Membrane Transduction." Clearly, the G-proteins represented in palpable form the "second messengers" postulated by Sutherland in the 1950s. Rodbell showed how these messengers operated in a more sophisticated conceptual framework. The G-proteins proved to be the essential components of the hormone signaling process.