G-proteins and the lung: nuts and bolts and out of the gutter.

The first documented description of inflammation as a distinct phenomenon dates back several centuries B.C. to preserved Mesopotamian clay tablets and Egyptian medical papyri [1]. Since then, through the eminent work by J.F. Cohnheim, E. Mechnikoff, T. Leber and many others thereafter, as well as the advances in modern molecular biology, the understanding of mechanisms underlying inflammation has made much progress. At the present time, inflammation may be adequately described as an extremely complex series of interdigitating processes, in a wide variety of combinations and permutations, which is presumably designed as a reparative and protective response to external noxae and tissue injury. The cornerstones of this dynamic pathophysiological host reaction are a variety both of circulating and constitutive cells, which communicate through an even more complex web of structural or soluble signals. To complicate matters further, it has become apparent that the net biological effect of intercellular messengers, or mediators, may be determined by microenvironmental factors and varies depending on the composition, as well as the state of degradation, of the surrounding matrix, the actual concentration of a particular signal achieved at tissue level, and the presence or absence of co-secrated mediators [2]. In addition, the biological outcome may ultimately depend on the state of activation and/or maturation of the individual target cell, which, in turn, may be regulated both by the cell itself (autocrine action), and other surrounding or distant cells (paracrine action). However, the principal molecular mechanisms by which the cell discriminates between the plethora of synergistic or antagonistic incoming signals have long remained obscure. When, during the 1950s, Sutherland discovered that epinephrine exerts its effects by stimulating the intracellular generation of a then unknown compound called cyclic adenosine monophosphate (cAMP), he unveiled the first of many secondary messengers [3]. It was for this discovery, that Sutherland received the 1971 Nobel prize. Although the precise mechanism by which epinephrine binding to its respective receptor might stimulate cAMP was unknown, it was generally assumed that the receptor directly signalled the cAMP-generating enzyme adenylate cyclase. However, as more cAMPstimulating receptors and secondary messengers were discovered, it became clear that this receptor-secondary messenger model could not account for the diversity in exogenous signals on the one hand and the cellular response on the other. It was left to the work of biochemist M. Rodbell of the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina, and the pharmacologist A.G. Gilman of the University of Texas Southwestern Medical Center in Dallas to discover another missing piece in the puzzle, which bridges the multitude of surface receptors and intracellular signalling pathways [4, 5] ultimately determining the individual cellular response in a given context. The cellular mechanisms of the physiological regulation have been the subject of intense research for some time, and certain principles of cellular pathways have emerged throughout the past decade or so. Utilization of intracellular calcium, cAMP and diacylglycerol (DAG), as well as the protein kinase cascades and the inositol phosphate cycle, represent well-established examples [6]. In addition, the interactive crosstalk of the major cell signalling systems at different levels between plasma membrane and gene transcription and cell cycle control are beginning to be unveiled. Due to the groundwork by Gilman and Rodbell, there is now substantial evidence that an increasing number of ubiquitous proteins, which are located close to the inner aspect of the cell membrane, may serve as a highly versatile molecular switch that regulate the seemingly infinite external signals and cellular signalling processes. According to their characteristic property of binding guanine nucleotides, they have collectively been termed Gproteins. G-proteins belong to a larger superfamily of guanosine triphosphases (GTPases) that include both factors controlling protein synthesis, of which the elongation factor-Tu (EF-Tu) has been studied most extensively, and a group of "small" guanosine triphosphate (GTP)binding proteins with a molecular mass of 20–25 kD. Members of the latter group include the ras gene product, the adenosine diphosphate (ADP)-ribosylation factor (ARF) (a co-factor for cholera toxin catalysed ADP-ribosylation of Gs), Gp (a GTP-binding protein purified from the placenta) the rho gene product, and products of yeast YPT1 and SEC4 genes. In contrast to the small G-proteins, classical G-proteins are heterotrimers composed of three distinct subunits EDITORIAL