Perspectives For The Future

Very soon we will know the identity of all the pieces in many signal-transduction pathways, but putting the puzzle together to predict cellular responses remains elusive. For instance, we can enumerate the G proteins, kinases, phos-phatases, arrestins, and other proteins that participate in signaling from p-adrenergic receptors in liver cells, but we are still far from being able to predict, quantitatively, how liver cells react over time to a given dose of adrenaline. In part this is because complex feedback (and in some cases feed-forward) loops regulate the activity of multiple enzymes and other components in the pathway. Although biochemical and cell biological experiments tell us how these interactions occur, we cannot describe quantitatively the rates or extent of these reactions in living cells.

The emerging field of biological systems analysis attempts to develop an integrated view of a cell's response to external signals. Mathematical equations are formulated that incorporate rate constants for enzyme catalysis, formation of proteinprotein complexes, and concentrations and diffusion rates of all the various signal-transduction proteins. These models incorporate information about changes in the subcellular localization of proteins with time (e.g., movement of transcription factors into the nucleus or endocytosis of surface receptors) and the effect on the activity of any given protein (e.g., glycogen phosphorylase) of the local Ca2+ concentration and the presence of multiple kinases and phosphatases. By comparing the results of such calculations with actual experimental results (say, by increasing or decreasing selectively the concentration of one component of the pathway) we can determine, in principle, whether we have accounted for all of the components of the pathway. Such mathematical modeling will also help the pharmaceutical industry develop new drugs that might activate or inhibit specific pathways. Modeling can enable one to extrapolate the results of experiments on drugs on proteins in test tubes or on cultured cells in order to predict their efficacy and side effects in living organisms.

In this chapter we focused primarily on signal-transduction pathways activated by individual G protein-coupled receptors. However, even these relatively simple pathways presage the more complex situation within living cells. As we've seen, activation of a single type of receptor often leads to production of multiple second messengers or activation of several types of downstream transducing proteins. Moreover, the same cellular response (e.g., glycogen breakdown) is affected by multiple signaling pathways activated by multiple types of receptors. Interaction of different signaling pathways permits the fine-tuning of cellular activities required to carry out complex developmental and physiological processes, and the ability of cells to respond appropriately to extracellular signals also depends on regulation of signaling pathways themselves.

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