Scientists On Science
Raven and Johnson's Biology, Sixth Edition

G Proteins

Alfred G. Gilman
Department of Pharmacology
University of Texas Southwestern Medical Center
Dallas, Texas

It is surely a sign of age to start this brief essay with reflections on how knowledge of G proteins has advanced during the two decades (nearly) since their discovery. We originally sought to understand mechanisms of regulation of cyclic AMP synthesis by hormones and neurotransmitters. We were rewarded in the late 1970s and early 1980s with the discovery, purification, and characterization of two G proteins, G_s and G_i, that are responsible for stimulatory and inhibitory regulation of adenylyl cyclase following their activation by appropriate receptors. During this period of time, Mark Bitensky, then at Yale University, had called attention to unexpected parallels between hormonal regulation of adenylyl cyclase and the initial events in perception of visual information. GTP was also involved in visual transduction, and the relevant G protein, transducin (or G_i), also emerged about this time. G proteins were thus on hand to account for the known phenomenology-requirements for GTP in these signaling systems.

If there was a period of complacency, it was brief. A new G protein was discovered by Paul Sternweis. Its startlingly high concentration in brain (100 times higher than G_s) spoke clearly of the unanticipated and very broad significance of G protein-regulated signaling systems. We now know that G proteins control such divergent phenomena as sexual mating in yeast and vision and cognition in humans. In mammals, roughly twenty different G protein a subunits are joined with distinct species of ß and g subunits to create hundreds of unique G protein heterotrimers.

G proteins lie at the heart of remarkably complex signaling switchboards in the cellular plasma membrane. Each cell designs (and modifies) its own custom switchboard by its choice of expression of components; the available catalog contains hundreds of receptors and dozens of effector molecules (adenylyl cyclases, phospholipases, channels, etc.) in addition to the G proteins. In many cases, there are closely related isoforms of a given functional entity that are expressed in a cell-specific fashion. By choosing between closely related isoforms of a given receptor, G protein, or effector, the cell can alter the extent of convergence or divergence of signal transmission through the switchboard. The existence of cell-specific isoforms of signaling components also provides enormous opportunities for development of cell-specific therapeutic drugs.

With DNA cloning and sequencing proceeding at a remarkable pace, one can easily envision the time when all of the components of these switchboards and detailed patterns of their cellular expression will be known with certainty. Many of the myriad interactions of these molecules and their consequences for cell function are well known today; the remainder will be defined thoroughly by the combined efforts of biochemists, geneticists, physiologists, and pharmacologists. This data base forms an increasingly profound substrate for future advances in therapeutics and rational drug design. The ability to create extraordinarily selective drugs to modify the specialized functions of individual types of cells will be greatly enhanced, particularly when coupled with modern techniques of combinatorial chemistry and drug design aided by atomic knowledge of receptor structure. The fruits of basic biological research will continue to be of enormous value to medicine. It is amazing that this tenet is ever questioned.

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