CHEMICAL BIOLOGY

Extracellular Lipid Signals

 

Jerold Chun, Helen L. Dorris Institute for Neurological and Psychiatric Disorder, Department of Molecular Biology, The Scripps Research Institute, La Jolla, California

doi: 10.1002/9780470048672.wecb289

 

Lipid molecules can act as extracellular signals. They form a large and expanding class of influences on cellular and organismal homeostasis, which affect all organ systems and participate in many disease processes. Prominent members of this class include eicosanoids (e.g., leukotrienes or prostanoids like prostaglandins, protacyclins, and thromboxane), lysophospholipids (e.g., lysophosphatidic acid and sphingosine 1-phosphate), endocannabinoids (e.g., anandamide and 2-arachidonoylglycerol), ether lipids (e.g., platelet activating factor), and free fatty acids. These signals are in a dynamic steady state with structural phospholipids that make up the lipid membrane bilayer of all cells. Both distinct and shared enzymologies are involved in lipid signal biosynthesis and degradation. A dominant mechanistic theme for all bona fide extracellular lipid signals is their use of cognate 7-transmembrane domain G protein-coupled receptors. Activation of these receptors causes myriad physiologic and pathophysiologic effects that encompass most aspects of cell biology and physiology. Studies on extracellular lipid signals have led to both mechanistic understanding and successful creation of useful medicines.

 

Extracellular lipid signals are small fat molecules that produce myriad cell signaling effects upon exposure to the extracellular surface of cells. The dominant mechanism for these effects is the activation of specific cognate cell surface receptors, called G protein-coupled receptors (GPCRs), which are characterized by a predicted 7-transmembrane-spanning structure and which activate most known, intracellular heterotrimeric G proteins. These G proteins in turn activate a wide range of downstream signaling pathways, with the actual physiologic responses dependent on receptor expression patterns and involved cell types. All of these lipid mediators are linked, directly or indirectly, to membrane phospholipids that can be thought of as a dynamic repository of signaling lipid precursors. A diverse, yet often overlapping, enzymatic machinery exists for both the biosynthesis and the degradation of these signals. Compared with peptidergic factors, lipid mediators are often one tenth or less in mass, and they have brief half-lives, although binding to carrier proteins can substantially increase their stability. Historically, the understanding of these factors emerged in two phases. The first phase, which began about 70 years ago and continues today, was the important biochemical identification of lipids that showed bioactive properties in animals, and could be chemically isolated and structurally analyzed. This phase was marked by many mechanistic hypotheses to explain the observed bioactivities, including nonreceptor hypotheses. Tools for the identification of lipid components include classic thin layer chromatography, liquid chromatography, mass spectroscopy, as well as the use of bioassays and isotope labeling.

The second phase began with the advent of molecular cloning of cell-surface lipid receptors that commenced in the late 1980s/early 1990s and that allowed rigorous assessment of the existence, pharmacology, and functional roles for extracellular lipid signaling. It included the use of genetics to create mouse mutants that allowed additional analyses of both receptor identity and essential physiologic or pathophysiologic roles. Most receptor-ligand interactions occur at nanomolar affinities, with the exception of free fatty acids that interact at micromolar concentrations. A mainstay of these studies is the use of modern cell and molecular biology leading to the creation of mutant cell lines and animals. A standard in all fields is the use of receptor overexpression or heterologous expression, particularly combined with the use of receptor-null cells and tissues created by targeted deletion of one or more of the receptors in question. Interestingly, deleting individual lipid receptors produces a variety of phenotypes, which demonstrates both