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About G proteins (c) 2001 PFPC Some backgound information... All animals, both vertebrates and invertebrates, produce a variety of factors including hormones, neurotransmitters, growth factors and other circulating, physiological mediators which are responsible for a wide variety of effects. These include stimulation or inhibition of protein synthesis, cell division, growth, neural transmission, tissue repair and maintenance, nutrient storage/release and the storage/release of other hormones or neurotransmitters. They share the common feature of being manufactured and released by cells and exerting their effects through cell surface receptors. Signal Transduction Signal transduction pathways maintain the balanced steady state functioning of a cell. Disease states occur when signal transduction in a cell breaks down, thereby removing the tight control that typically exists over cellular functions. For example, tumors develop when regulation of cell growth is disrupted enabling a clone of cells to expand indefinitely. Because signal transduction networks regulate a multitude of cellular functions depending upon the cell type, a wide variety of diseases can result from even slight abnormalities in such networks. Devastating diseases such as cancer, autoimmune diseases, allergic reactions, inflammation, neurological disorders and hormone-related diseases can result from abnormal signal transduction. A signal transduction pathway in a cell can be initiated by interaction of a cell with a stimulator that is inside or outside of the cell. If an exterior (outside of the cell) stimulator interacts with a cell surface receptor, a signal transduction pathway transmits a signal across the cell's membrane, through the cytoplasm of the cell, and in some instances right into the nucleus. If an interior (inside the cell) stimulator interacts with an intracellular signal transduction molecule, a signal transduction pathway can result in transmission of a signal through the cell's cytoplasm, and in some instances into the cell's nucleus. Hormones and growth factors act initially by binding to a receptor protein, which may be located either on the surface or in the cytoplasm of the particular factor's target cell. The receptor has a binding site which has a high affinity and specificity for the growth factor or hormone; when the binding between factor and receptor occurs, a sequence of reactions (a "cascade") is initiated which alters the functioning of the target cell. For example, it may cause the target cell to increase production and secretion of a particular protein, or alternately, it may signal the target cell to temporarily cease or decrease production of a certain protein. These activities are regulated by switches called G proteins. G Proteins In essence, G proteins are "On/Off" switches which regulate cellular communication - relaying information received from outside the cell to the inside, or from one cell to another.They are called G proteins because they bind to guanine nucleotides, a major component of the DNA and RNA, comprised of an organic base (guanine), a sugar and one or more phosphates. This process of cell communication is called "signal transduction", a term first applied in molecular biology by Martin Rodbell, who with Alfred Gilman received the 1994 Nobel Prize in medicine and physiology for their independent work leading to the discovery of G proteins. The G protein design explains how such extracellular "first messengers" as hormones generate intracellular "second messengers" such as cyclic AMP (cAMP) or Ca(2+), an idea originally proposed by Earl Sutherland in the 1950s (Nobel Prize,1971). In turn, these "second messengers" alter the behaviour of other target proteins within the cell, which then can influence the way the cell communicates growth or inhibition to other cells, or within its own environment. Rodbell had compared the fundamental information processing system in the biological organism to that of a computer, a metaphor which he used throughout his carreer. A computer performs its tasks by turning on and off a series of electronic switches which are represented as a series of 1 (on) and 0 (off). Using the analogy of the "transducer", Rodbell described how individual cells were made up of three distinct molecular components: discriminators (receptors), transducers, and amplifiers (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 (1). Rodbell further used his "computer" metaphor describing the concept of working cells as "programmable messengers". Since it became known that many activities of G proteins are reversible, research on G protein-mediated pathways has been one of the hottest biological pursuits of the past decades, mainly because of experience gained from the advanced research into G proteins as such "programmable messengers". In 1996 pharmacologists estimated that up to 60% of all medicines used exerted their effects through G protein signaling pathways (2). Manipulation of receptor function is a way in which the action of the signalling compound can be modulated. For example, if in a given situation the ultimate effect of a hormone or growth factor is undesirable, blocking or otherwise interfering with receptor binding and G protein activity will prevent this action. Similarly, there are situations in which it may be desirable to increase the numbers of receptor sites in certain cell types or to place a specific receptor in a cell type which had not previously expressed it. A few year prior to receiving the 1994 Nobel prize, Gilman and co-author Maurine Linder had predicted that scientists would eventually diagram the cellular players involved in communication and be able to predict how those cells will operate in response to different combinations of signals. "For those who would hope to develop drug therapies such discoveries would be like giving a thief a wiring diagram to the alarm system at a bank", the authors wrote (3). Rodbell shared similar concerns. In a press conference in Maryland, following the announcement of the 1994 Nobel Prize, he critized the current state of the commercialization of science. . ."The tenor is changed, the world ain't the same, everything is targeted, everything is bottom line, how to make a buck, " he said, adding that it is crucial to "capture knowledge for its own sake and for humanity" (4). REFERENCES: 1) NIH - Rodbell Papers RODBELL AND G Proteins "Signal Transduction and the RODBELL AND G PROTEINS #2 (1981-1994) RODBELL PROFILE AND PAPERS 2) Roush W - "Regulating G protein signaling" Science 271 (5252):1056-8 (1996) 3) Linder ME, Gilman AG - "G proteins" Sci Am 267(1):56-61, 64-5 (1992) 4) BOSTON GLOBE, October 11, 1994 See also:
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